Compositions and Methods for Inhibiting Gene Expression of Factor XII

ABSTRACT

RNA interference (RNAi) triggers for inhibiting the expression of Factor XII (F12) gene through the mechanism of RNA interference are described. Pharmaceutical compositions comprising one or more F12 RNAi triggers together with one or more excipients capable of delivering the RNAi trigger(s) to a liver cell in vivo are also described. Delivery of the F12 RNAi trigger(s) to liver cells in vivo provides for inhibition of F12 gene expression and treatment of angioedema, including hereditary angioedema (HAE) and venous thromboembolism (VTE), and diseases associated with angioedema.

BACKGROUND

Factor XII, a serine protease expressed predominantly in the liver andfound in blood, has dual functions in both the intrinsic coagulationpathway and the kinin-kallikrein system. The kinin-kallikrein systemplays a role in inflammation, blood pressure control, coagulation andpain. The active form of Factor XII (also referred to as FXII, F12, orHageman factor) binds and cleaves both Factor XI in the coagulationcascade and prekallikrein in the kinin-kininogen system, yielding theactive forms FXI and kallikrein, respectively.

Patients with complete loss of F12 do not present with a bleedingdisorder. Further, mice lacking F12 by gene knockout are protected fromthrombosis (Renne et al JEM 2005, 202:271-281). The thrombo-protectiveeffect of F12 depletion was also observed in F12-inhibitory antibodytreated mice, rabbits and primates (Larsson et al. ScienceTransMed, 20146:22ra17). Current treatments for thromboembolic events target enzymesdownstream in the coagulation pathway that are critical for controllinginjury-related blood loss through fibrin formation, and therefore,treatment with these agents have the downside of potentiallife-threatening hemorrhage.

Hereditary angioedema (HAE) is a rare disease characterized by recurrentepisodes of severe swelling. The most common areas of the body todevelop swelling are the limbs, face, intestinal tract, and airway.Episodes may be spontaneous or be induced by physical trauma or stress.Laryngeal (airway) edema can be life-threatening, as it can lead todeath by asphyxiation.

The majority of HAE treatment options are for administration at the timeof attack, focusing on either C1INH replacement, inhibiting kallikrein,or signaling through the bradykinin 2 receptor. Currently, the onlylong-term prophylactic treatment is C1INH replacement therapy. Becauseboth thrombosis (including venous thromboembolism, VTE) and angioedemaare thought to occur through overactive signaling of their respectivepathways, inhibition of F12 gene expression would be useful inpreventing both types of disorders.

SUMMARY

Described herein are F12 RNA interference (RNAi) triggers andcompositions thereof for inhibiting expression of the F12 gene in vivo.The F12 RNAi triggers described herein can be used for treating diseasescaused by over-activation of the kinin-kallikrein and intrinsiccoagulation pathways, such as HAE and thrombosis.

Described herein are Factor XII (also termed Factor 12, F12, or Hagemanfactor) gene-specific RNA interference (RNAi) trigger molecules (alsotermed RNAi agent, RNAi trigger, or trigger) able to selectively andefficiently decrease expression of F12. Use of the described. F12 RNAitriggers can be used in methods for therapeutic treatment of diseasesassociated with angioedema, including but not limited to: hereditaryangioedema (HAE), acquired angioedema (AAE), ACE inhibitor associatedangioedema, allergic angioedema, nonhistaminergic angioedema (INAE),idiopathic angioedema, thrombosis, venous thromboembolism (VTE),thrombotic occlusive disease, pen-operative venous occlusive diseaseprophylaxis. Use of the described F12 RNAi triggers further providesmethods for the treatment and prevention of venous occlusive diseasesuch as deep venous thrombosis or pulmonary embolism, and treatment orprevention of arterial thromboembolic disease. Such methods compriseadministration of an F12 RNAi trigger as described herein to a subject,e.g., a human or animal subject.

RNAi triggers for inhibiting expression of the human F12 gene (F12 RNAitriggers) are described herein. Each RNAi trigger includes at least asense strand and an antisense strand. The sense strand and the antisensestrand can be partially, substantially, or fully complementary to eachother. The length of the RNAi trigger sense and antisense strandsdescribed herein each can be 16 to 30 nucleotides in length. In someembodiments, the sense and antisense strands each can be 17 to 26nucleotides in length. The sense and antisense strands can be either thesame length or different lengths. In some embodiments, both the senseand antisense strands each can be 26 nucleotides in length. In otherembodiments, the sense strand is about 23 nucleotides in length whilethe antisense strand is about 21 nucleotides in length. In someembodiments, the sense and antisense strands are 17 nucleotides inlength. The RNAi triggers described herein, upon delivery to a cellexpressing the F12 gene, inhibit the expression of the F12 gene in vitroor in vivo.

A sense strand of the F12 RNAi triggers described herein contains anucleotide sequence having at least 90% identity to a sequence in an F12mRNA. In some embodiments, the nucleotide sequence having at least 90%identity to a sequence in an F12 mRNA is 16, 17, 18, 19, 20, 21, 22, 23,24, 25, or 26 nucleotides in length. An antisense strand of the F12 RNAitriggers described herein contains a nucleotide sequence having at least90% complementary to a sequence in an F12 mRNA. In some embodiments, thenucleotide sequence having at least 90% complementarity to a sequence inan F12 mRNA is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotidesin length. Examples of F12 RNAi trigger sense strands and antisensestrands that can be used in a F12 RNAi trigger are provided in Tables1-3.

In some embodiments, one or more F12 RNAi triggers are delivered totarget cells or tissues using any oligonucleotide delivery technologyknown in the art. Nucleic acid delivery methods include, but are notlimited to, by encapsulation in liposomes, by iontophoresis, or byincorporation into other vehicles, such as hydrogels, cyclodextrins,biodegradable nanocapsules, and bioadhesive microspheres, proteinaceousvectors or DPCs (see, for example WO 2000/053722, WO 2008/0022309, WO2011/104169, and WO 2012/083185, each of which is incorporated herein byreference). In some embodiments, an F12 RNAi trigger is covalentlylinked to a targeting group. The targeting group can include a cellreceptor ligand, such as a galactose cluster, including a galactosecluster comprised of an N-acetyl-galactosamine trimer, or a hydrophobicgroup, such as a cholesterol. In some embodiments, an F12 RNAi triggeris provided with an in vivo delivery compound or vehicle. The deliverycompound or vehicle can include a polymer, such as a melittin-likepeptide (MLP) delivery polymer or copolymer. In some embodiments, an F12RNAi trigger can be covalently linked to a delivery compound or vehicle.

The F12 RNAi triggers or pharmaceutical compositions containing one ormore F12 RNAi triggers can be administered in a number of ways dependingupon whether local or systemic treatment is desired and upon the area tobe treated. In some embodiments, administration is topical (e.g., by atransdermal patch), pulmonary, e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer: intratracheal, intranasal,epidermal and transdermal, oral or parenteral. Parenteral administrationincludes intravenous, intraarterial, subcutaneous, intraperitoneal orintramuscular injection or infusion; subdermal, e.g., via an implanteddevice; or intracranial, e.g., by intraparenchymal, intrathecal orintraventricular, administration.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Graphs showing: A. Serum F12 protein levels in wild-type micefollowing administration of 2 mg/kg RNAi trigger with 2 mg/kg MLPdelivery polymer, and B. Serum F12 protein levels in wild-type micefollowing administration of 4 mg/kg RNAi trigger with 4 mg/kg MLPdelivery polymer. mF12 levels were normalized to day 1 and salinecontrol.

FIG. 2. Graph showing serum F12 protein levels in wild-type micefollowing administration of 1, 2, or 4 mg/kg F12 RNAi trigger dosed 1:1wt./wt. with MLP delivery polymer. mF12 levels were normalized to day 1and saline control.

FIG. 3. Graph showing serum F12 protein levels in wild-type micefollowing a single subcutaneous (SQ) administration of 1, 3, or 10 mg/kgRNAi trigger on day 1. mF12 levels were normalized to day 1 and salinecontrol.

FIG. 4. Graph showing serum F12 protein levels in wild-type micefollowing SQ administration of 1 or 2 mg/kg RNAi trigger on days 1, 8and 15. mF12 levels were normalized to day 1 and saline control.

FIG. 5. Graph showing serum F12 protein levels in cynomolgus monkeysfollowing administration of a single 2 mg/kg RNAi trigger dosed 1:1wt./wt. with MLP delivery polymer on day 1. cF12 levels were normalizedto day 1. F12 RNAi trigger AD01001 is shown in black circles, F12 RNAitrigger AD01520 is shown in gray squares. Standard Deviation isdisplayed as error bars graphed above the mean.

FIG. 6. Graph showing serum F12 protein levels in cynomolgus monkeysfollowing administration of 2 mg/kg RNAi trigger dosed 1:1 with MLPdelivery polymer on day 1, 29, 57, and 85. cF12 levels were normalizedto day 1. F12 RNAi trigger AD01001 is shown in black circles, F12 RNAitrigger AD01520 is shown in gray squares. Standard deviation isdisplayed as error bars graphed above the mean.

FIG. 7. Graph showing serum F12 protein levels in cynomolgus monkeysfollowing administration of 4 mg/kg F12 RNAi trigger AD01520 dosed 1:1with MLP delivery polymer on day 1, 29, 57, 85, and 121. cF12 levelswere normalized to day 1. cF12 levels are graphed in gray squares, aPTTis shown in black circles. Standard deviation is displayed as error barsgraphed above the mean.

FIG. 8. Graph showing serum F12 protein levels in cynomolgus monkeysfollowing single subcutaneous administration of 3 mg/kg or 10 mpg of F12RNAi trigger AD02562 on day 1. cF12 levels were normalized to day 1.3mg/kg dose is shown in gray squares, 10 mg/kg dose is shown in blackcircles. Standard deviation is displayed as error bars graphed above themean.

FIG. 9. Graph showing change in rat paw volume after carrageenaninjection in rats treated seven days prior to carrageenan injection witheither saline, or 8 mg/kg F12 RNAi trigger AD01520 with 8 mg/kg MLPdelivery polymer. A. Shows change in paw volume in treated vs. salineanimals. B. Shows level of knockdown in treated vs. saline animals.

FIG. 10. Graph showing: A. Time to occlusion after ferric chloridechallenge in mice treated seven days prior to ferric chloride challengewith either saline, or 8 mg/kg F12 RNAi trigger AD01520 with 8 mg/kg MLPdelivery polymer. All animals in the RNAi trigger-treated group did notocclude during the time of the experiment (30 minutes, noted by dashedline). B. Knockdown in animals treated with F12 RNAi trigger AD01520with MLP delivery polymer, compared to animals treated with saline.

FIG. 11. Graphs showing: A. Bleeding times of mice treated with eithersaline, 8 mg/kg F7-targeted RNAi trigger with 8 mg/kg MLP deliverypolymer, or 8 mg/kg F12 RNAi trigger AD01520 with 8 mg/kg MLP deliverypolymer. B. F12 protein levels. C. F7 protein levels.

DETAILED DESCRIPTION

Described herein are RNAi triggers for inhibiting expression of theFactor XII gene (referred to herein as F12 RNAi triggers). An F12 RNAitriggers each comprise a sense strand and an antisense strand. The sensestrand and the antisense strand are partially, substantially, or fullycomplementary to each other. In some embodiments, the length of theherein described RNAi trigger sense and antisense strands areindependently 16 to 30 nucleotides in length. In some embodiments, thelength of the herein described RNAi trigger sense and antisense strandsare independently 17 to 26 nucleotides in length. In some embodiments,the herein described RNAi trigger sense and antisense strands areindependently 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides inlength. The sense and antisense strands can be either the same length orthey can be different lengths. In some embodiments, both the sense andantisense strands are each 26 nucleotides in length. In otherembodiments, the sense strand is about 23 nucleotides in length whilethe antisense strand is about 21 nucleotides in length. In otherembodiments, the sense and antisense strands are independently 17-21nucleotides in length. Examples of nucleotide sequences used in formingF12 RNAi trigger molecules are provided in Tables 1-3.

RNAi triggers include, but are not limited to: short interfering RNAs(siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpinRNAs (shRNA), and dicer substrates (U.S. Pat. No. 8,084,599 8,349,809and 8,513,207). The RNAi triggers described herein, upon delivery to acell expressing the F12 gene, inhibit or knockdown expression of F12gene in vitro or in vivo through the biological process of RNAinterference (RNAi).

An F12 RNAi trigger comprises a sense strand and an antisense strandeach containing a core sequence of 16-23 nucleobases in length. Anantisense strand core sequence is 100% (perfectly) complementary or atleast 90% (substantially) complementary to a nucleotide sequence(sometimes referred to, e.g. as a target sequence) present in the F12mRNA. A sense strand core sequence is 100% (perfectly) complementary orat least 90% (substantially) complementary to a sequence in theantisense strand and thus the sense strand core sequence is perfectlyidentical or at least 90% identical to a nucleotide sequence (targetsequence) present in the F12 mRNA. A sense strand core sequence can bethe same length as a corresponding antisense core sequence or it can bea different length. In some embodiments, the antisense strand coresequence is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In someembodiments, the sense strand core sequence is 17, 18, 19, 20, 21, 22,or 23 nucleotides in length.

The F12 RNAi trigger sense and antisense strands typically anneal toform a duplex. Within the complementary duplex region, the sense strandcore sequence is at least 90% complementary or 100% complementary to theantisense core sequence. In some embodiments, the sense strand coresequence contains a sequence of at least 16, at least 17, at least 18,at least 19, at least 20, or at least 21 nucleotides that is at least90% or 100% complementary to a corresponding 16, 17, 18, 19, 20, or 21nucleotide sequence of the antisense strand core sequence (i.e., thesense strand and antisense core sequences of an F12 RNAi trigger have aregion of at least 16, at least 17, at least 18, at least 19, at least20, or at least 21 nucleotides that is at least 90% base paired or 100%base paired.)

The sense strand and/or the antisense strand may optionally andindependently contain an additional 1, 2, 3, 4, 5, or 6 nucleotides(extension) at the 3′ end, the 5′ end, or both the 3′ and 5′ ends of thecore sequences. The antisense strand additional nucleotides, if present,may or may not be complementary to the corresponding sequence in the F12mRNA. The sense strand additional nucleotides, if present, may or maynot be identical to the corresponding sequence in the F12 mRNA. Theantisense strand additional nucleotides, if present, may or may not becomplementary to the corresponding sense strands additional nucleotides,if present.

As used herein, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotidesat the 5′ and/or 3′ end of the sense strand core sequence and/orantisense strand core sequence. The extension nucleotides on a sensestrand may or may not be complementary to nucleotides, either coresequence nucleotides or extension nucleotides, in the correspondingantisense strand. Conversely, the extension nucleotides on an antisensestrand may or may not be complementary to nucleotides, either coresequence nucleotides or extension nucleotides, in the correspondingsense strand. In some embodiments, both the sense strand and theantisense strand of an RNAi trigger contain 3′ and 5′ extensions. Insome embodiments, one or more of the 3′ extension nucleotides of onestrand base pairs with one or more 5′ extension nucleotides of the otherstrand. In other embodiments, one or more of 3′ extension nucleotides ofone strand do not base pair with one or more 5′ extension nucleotides ofthe other strand. In some embodiments, an F12 RNAi trigger has anantisense strand having a 3′ extension and a sense strand having a 5′extension.

In some embodiments an F12 RNAi trigger molecule comprises an antisensestrand having a 3′ extension of 1, 2, 3, 4, 5, or 6 nucleotides inlength. In other embodiments, an F12 RNAi trigger molecule comprises anantisense strand having a 3′ extension of 1, 2, or 3 nucleotides inlength. In some embodiments, one or more of the antisense strandextension nucleotides comprise uracil or thymidine nucleotides ornucleotides which are complementary to the corresponding F12 mRNAsequence. In some embodiments, the antisense strand extension can be,but is not limited to: uAu, uGu, udTsdT, usdTsdT, UfAu, Aua, Afsusa,UAU, uAfu, uau, udAu, uscu, usgu, uscsu, cAu, aUa, aua, u(invdA)u, cag,agu, gcg, caa, usasu, uAMTM, usTMsAM (each listed 5′ to 3′, notation isthe same as for Tables 2 and 3).

In some embodiments, an F12 RNAi trigger molecule comprises an antisensestrand having a 5′ extension of 1, 2, 3, 4, or 5 nucleotides in length.In other embodiments, an F12 RNAi trigger molecule comprises anantisense strand having a 5′ extension of 1 or 2 nucleotides in length.

In some embodiments, one or more of the antisense strand extensionnucleotides comprises uracil or thymidine nucleotides or nucleotideswhich are complementary to the corresponding F12 mRNA sequence. In otherembodiments, the antisense strand extension includes or consists of dA,dT, pdT, vpdT, or u, wherein dA and di represent deoxyadenosine anddeoxythimidine nucleotides respectively, pdT represents a deoxythimidinenucleotide having a 5′ phosphosphate, vpdT represents a vinylphosphonatedeoxythimidine nucleotide, and u represents a 2′-OMe modified uracilnucleotide. An antisense strand may have any of the 3′ extensionsdescribed above in combination with any of the 5′ antisense strandextensions described, if present.

In some embodiments, an F12 RNAi trigger molecule comprises a sensestrand having a 3′ extension of 1, 2, 3, 4, or 5 nucleotides in length.In some embodiments, one or more of the sense strand extensionnucleotides comprises adenosine, uracil, or thymidine nucleotides, ATdinucleotide, or nucleotides which correspond to nucleotides in the F12mRNA sequence. In other embodiments, the 3′ sense strand extensionconsists of Af, invdA, invdT, A(invdT), Af(invdT), U(invdT), Uf(invdT),AfAbuAu, dTdT, or dTsdT, wherein Af and Uf represent 2′-fluoro adenosineand uracil nucleotides respectively, invdA and invdT represent 3′-3′linked (inverted) deoxyadenosine and deoxythimidine nucleotidesrespectively, Ab represents an abasic ribose, u represents a 2′-OMemodified uracil nucleotide, dT represents a deoxythimidine nucleotide,sdT represents a deoxythimidine nucleotide having a 5′ phosphorothioate,and U and A represent uracil and adenosine ribonucleotides.

In some embodiments, an F12 RNAi trigger molecule comprises a sensestrand having a 5′ extension of 1, 2, 3, 4, 5, or 6 nucleotides inlength. In some embodiments, one or more of the sense strand extensionnucleotides comprise uracil or adenosine nucleotides or nucleotideswhich correspond to nucleotides in the F12 tnRNA sequence. In someembodiments, the sense strand 5′ extension can be, but is not limitedto: uAuAus, uAuAu, UAUUAGfs, UfaUfaA, uauaA, AUAUU, AfuAfuU, auauU,uaUfau, uAuA(U_(UNA)), uauau, udAudAu, uuAga, uuAuu, uuGAu, uuaga,uAuga, aUaGas, uauaus, uAuaas, udAuau, adTaga, auaga, u(invdA)uau,gacau, ugaau, gcgau, uauga, uugga, auaga (each listed 5′ to 3′, notationis the same as for Tables 2 and 3). A sense strand may have a 3′extension and/or a 5′ extension.

Unmodified F12 RNAi trigger sense strand and antisense strand sequencesare provided in Table 1. Note that in each row, the antisense strand isnot necessarily shown with the corresponding (complementary) sensestrand. In forming F12 RNAi triggers, each of the nucleotides in each ofthe sequences listed in Table 1 may be a modified nucleotide.

TABLE 1 Unmodified F12 RNAi trigger antisense strand and sense strandsequences. SEQ ID SEQ ID No. Antisense Sequence (5′ → 3′) No. SenseSequence (5′ → 3′) 1 TGGUGGUAGCACACCAGGGTT 225 CCCUGGUGUGCUACCACCAT 2TGGGUGGUAGCACACCAGGTT 226 CCUGGUGUGCUACCACCCAT 3 TGGGGUGGUAGCACACCAGTT227 CUGGUGUGCUACCACCCCAT 4 TCACUUUCUUGGGCUCCAATT 228UUGGAGCCCAAGAAAGUGAT 5 TUCACUUUCUUGGGCUCCATT 229 UGGAGCCCAAGAAAGUGAAT 6TUUCACUUUCUUGGGCUCCTT 230 GGAGCCCAAGAAAGUGAAAT 7 TUUUCACUUUCUUGGGCUCTT231 GAGCCCAAGAAAGUGAAAAT 8 TCUUUCACUUUCUUGGGCUTT 232AGCCCAAGAAAGUGAAAGAT 9 TUCUUUCACUUUCUUGGGCTT 233 GCCCAAGAAAGUGAAAGAAT 10TGUCUUUCACUUUCUUGGGTT 234 CCCAAGAAAGUGAAAGACAT 11 TGGUCUUUCACUUUCUUGGTT235 CCAAGAAAGUGAAAGACCAT 12 TUGGUCUUUCACUUUCUUGTT 236CAAGAAAGUGAAAGACCAAT 13 TAGCUGAGGCUCAAAGCACTT 237 GUGCUUUGAGCCUCAGCUAT14 TAAGCUGAGGCUCAAAGCATT 238 UGCUUUGAGCCUCAGCUUAT 15TGAAGCUGAGGCUCAAAGCTT 239 GCUUUGAGCCUCAGCUUCAT 16 TGAGAAGCUGAGGCUCAAATT240 UUUGAGCCUCAGCUUCUCAT 17 TGCAGGCCUGGCUGGCCAGTT 241CUGGCCAGCCAGGCCUGCAT 18 TGCCCCCUCGAACUGGUGGTT 242 CCACCAGUUCGAGGGGGCAT19 TUUGCGGUCACCACAGCCCTT 243 GGGCUGUGGUGACCGCAAAT 20TGUUGCGGUCACCACAGCCTT 244 GGCUGUGGUGACCGCAACAT 21 TUGUUGCGGUCACCACAGCTT245 GCUGUGGUGACCGCAACAAT 22 TUUGUUGCGGUCACCACAGTT 246CUGUGGUGACCGCAACAAAT 23 TCUUGUUGCGGUCACCACATT 247 UGUGGUGACCGCAACAAGAT24 TGCUUGUUGCGGUCACCACTT 248 GUGGUGACCGCAACAAGCAT 25TGGCUUGUUGCGGUCACCATT 249 UGGUGACCGCAACAAGCCAT 26 TAAGCACUUUAUUGAGUUCTT250 GAACUCAAUAAAGUGCUUAT 27 TAAAGCACUUUAUUGAGUUTT 251AACUCAAUAAAGUGCUUUAT 28 TCAAAGCACUUUAUUGAGUTT 252 ACUCAAUAAAGUGCUUUGAT29 TUCAAAGCACUUUAUUGAGTT 253 CUCAAUAAAGUGCUUUGAAT 30TUUCAAAGCACUUUAUUGATT 254 UCAAUAAAGUGCUUUGAAAT 31 TUUUCAAAGCACUUUAUUGTT255 CAAUAAAGUGCUUUGAAAAT 32 TUUUUCAAAGCACUUUAUUTT 256AAUAAAGUGCUUUGAAAAAT 33 TCAUCCGUCCGUUGGUCCATT 257 UGGACCAACGGACGGAUGAT34 TGCAUCCGUCCGUUGGUCCTT 258 GGACCAACGGACGGAUGCAT 35TGGCAUCCGUCCGUUGGUCTT 259 GACCAACGGACGGAUGCCAT 36 TUGGCAUCCGUCCGUUGGUTT260 ACCAACGGACGGAUGCCAAT 37 TAUGGCAUCCGUCCGUUGGTT 261CCAACGGACGGAUGCCAUAT 38 TCAUGGCAUCCGUCCGUUGTT 262 CAACGGACGGAUGCCAUGAT39 TUCAUGGCAUCCGUCCGUUTT 263 AACGGACGGAUGCCAUGAAT 40TCUCAUGGCAUCCGUCCGUTT 264 ACGGACGGAUGCCAUGAGAT 41 TCAGAGCCCUCAUGGCAUCTT265 GAUGCCAUGAGGGCUCUGAT 42 TGCAGAGCCCUCAUGGCAUTT 266AUGCCAUGAGGGCUCUGCAT 43 TACCCCAGGAGCAGCAGAGTT 267 CUCUGCUGCUCCUGGGGUAT44 TGGGAAGUGGCAGGGCUCCTT 268 GGAGCCCUGCCACUUCCCAT 45TUGGUACAGCUGCCGGUGGTT 269 CCACCGGCAGCUGUACCAAT 46 TCUGGUCCUGAUCAAAGUUTT270 AACUUUGAUCAGGACCAGAT 47 TGCUGGUCCUGAUCAAAGUTT 271ACUUUGAUCAGGACCAGCAT 48 TUCGCUGGUCCUGAUCAAATT 272 UUUGAUCAGGACCAGCGAAT49 TCCAUCGCUGGUCCUGAUCTT 273 GAUCAGGACCAGCGAUGGAT 50TCCCAUCGCUGGUCCUGAUTT 274 AUCAGGACCAGCGAUGGGAT 51 TUCCCCAUCGCUGGUCCUGTT275 CAGGACCAGCGAUGGGGAAT 52 TCUUUCUUGGGCUCCAAACTT 276GUUUGGAGCCCAAGAAAGAT 53 TACUUUCUUGGGCUCCAAATT 277 UUUGGAGCCCAAGAAAGUAT54 TCUGAGCCCGCGGCCAUCATT 278 UGAUGGCCGCGGGCUCAGAT 55TUCCGAGGCCCACGGCUGATT 279 UCAGCCGUGGGCCUCGGAAT 56 TCUCCGAGGCCCACGGCUGTT280 CAGCCGUGGGCCUCGGAGAT 57 TCCUCCGAGGCCCACGGCUTT 281AGCCGUGGGCCUCGGAGGAT 58 TGGUGGCCUCCGAGGCCCATT 282 UGGGCCUCGGAGGCCACCAT59 TAGGUGGCCUCCGAGGCCCTT 283 GGGCCUCGGAGGCCACCUAT 60TUAGGUGGCCUCCGAGGCCTT 284 GGCCUCGGAGGCCACCUAAT 61 TGUAGGUGGCCUCCGAGGCTT285 GCCUCGGAGGCCACCUACAT 62 TGUCCCCAGUUCCGCGCUUTT 286AAGCGCGGAACUGGGGACAT 63 TUUCCGGCAGAAGGCGUGGTT 287 CCACGCCUUCUGCCGGAAAT64 TGUUCCGGCAGAAGGCGUGTT 288 CACGCCUUCUGCCGGAACAT 65TGGUUCCGGCAGAAGGCGUTT 289 ACGCCUUCUGCCGGAACCAT 66 TCCGGGUUCCGGCAGAAGGTT290 CCUUCUGCCGGAACCCGGAT 67 TUCCGGGUUCCGGCAGAAGTT 291CUUCUGCCGGAACCCGGAAT 68 TGUCCGGGUUCCGGCAGAATT 292 UUCUGCCGGAACCCGGACAT69 TUGUCCGGGUUCCGGCAGATT 293 UCUGCCGGAACCCGGACAAT 70TCGUUGUCCGGGUUCCGGCTT 294 GCCGGAACCCGGACAACGAT 71 TUCGUUGUCCGGGUUCCGGTT295 CCGGAACCCGGACAACGAAT 72 TUUCCUGGUCAGGGAAGGCTT 296GCCUUCCCUGACCAGGAAAT 73 TGUUCCUGGUCAGGGAAGGTT 297 CCUUCCCUGACCAGGAACAT74 TCGUUCCUGGUCAGGGAAGTT 298 CUUCCCUGACCAGGAACGAT 75TCCGUUCCUGGUCAGGGAATT 299 UUCCCUGACCAGGAACGGAT 76 TGCCGUUCCUGGUCAGGGATT300 UCCCUGACCAGGAACGGCAT 77 TCAGUGGGCCGUUCCUGGUTT 301ACCAGGAACGGCCCACUGAT 78 TAGCUCAGUGGGCCGUUCCTT 302 GGAACGGCCCACUGAGCUAT79 TGAAGACAGACUCUUGCGGTT 303 CCGCAAGAGUCUGUCUUCAT 80TUGCCGGCGCAGAAACUGUTT 304 ACAGUUUCUGCGCCGGCAAT 81 TGGCGAUGAGGCUGCCGGCTT305 GCCGGCAGCCUCAUCGCCAT 82 TGGGCGAUGAGGCUGCCGGTT 306CCGGCAGCCUCAUCGCCCAT 83 TGGGGCGAUGAGGCUGCCGTT 307 CGGCAGCCUCAUCGCCCCAT84 TACCCAGCAGGGGGCGAUGTT 308 CAUCGCCCCCUGCUGGGUAT 85TGCACCCAGCAGGGGGCGATT 309 UCGCCCCCUGCUGGGUGCAT 86 TAGCACCCAGCAGGGGGCGTT310 CGCCCCCUGCUGGGUGCUAT 87 TUCAGCACCCAGCAGGGGGTT 311CCCCCUGCUGGGUGCUGAAT 88 TCCGAGCACCACCGUCAGATT 312 UCUGACGGUGGUGCUCGGAT89 TGGCCGAGCACCACCGUCATT 313 UGACGGUGGUGCUCGGCCAT 90TUGGCCGAGCACCACCGUCTT 314 GACGGUGGUGCUCGGCCAAT 91 TUCCUGGCCGAGCACCACCTT315 GGUGGUGCUCGGCCAGGAAT 92 TCAGCUGCCGUCCGCAUCCTT 316GGAUGCGGACGGCAGCUGAT 93 TGGAGCGCGCAGCUGCCGUTT 317 ACGGCAGCUGCGCGCUCCAT94 TACGUAAGGCGACAGGAGCTT 318 GCUCCUGUCGCCUUACGUAT 95TCUGAACGUAAGGCGACAGTT 319 CUGUCGCCUUACGUUCAGAT 96 TCUGGCAUAUUCCUCCGCCTT320 GGCGGAGGAAUAUGCCAGAT 97 TAGCUGGCAUAUUCCUCCGTT 321CGGAGGAAUAUGCCAGCUAT 98 TGAAGCUGGCAUAUUCCUCTT 322 GAGGAAUAUGCCAGCUUCAT99 TGGAAGCUGGCAUAUUCCUTT 323 AGGAAUAUGCCAGCUUCCAT 100TCGGGCCUCCGGAAUCACCTT 324 GGUGAUUCCGGAGGCCCGAT 101 TGCCACUCUCUCACUGCGGTT325 CCGCAGUGAGAGAGUGGCAT 102 TAGCCACUCUCUCACUGCGTT 326CGCAGUGAGAGAGUGGCUAT 103 TAACAGAGCCGUCAUGGCGTT 327 CGCCAUGACGGCUCUGUUAT104 TCAACAGAGCCGUCAUGGCTT 328 GCCAUGACGGCUCUGUUGAT 105TACAACAGAGCCGUCAUGGTT 329 CCAUGACGGCUCUGUUGUAT 106 TAACAACAGAGCCGUCAUGTT330 CAUGACGGCUCUGUUGUUAT 107 TGAACAACAGAGCCGUCAUTT 331AUGACGGCUCUGUUGUUCAT 108 TGGAACAACAGAGCCGUCATT 332 UGACGGCUCUGUUGUUCCAT109 TCGGUGGUACUGAAAGGGATT 333 UCCCUUUCAGUACCACCGAT 110TUUGUGGAUGCAUUUGUGGTT 334 CCACAAAUGCAUCCACAAAT 111 TCAAGCAGUAUCCCCAUUGTT335 CAAUGGGGAUACUGCUUGAT 112 TCUCCAAGCAGUAUCCCCATT 336UGGGGAUACUGCUUGGAGAT 113 TGCUCCAAGCAGUAUCCCCTT 337 GGGGAUACUGCUUGGAGCAT114 TGGGCUCCAAGCAGUAUCCTT 338 GGAUACUGCUUGGAGCCCAT 115TGUGUUUGCUGCAAUGGUCTT 339 GACCAUUGCAGCAAACACAT 116 TUUCCGGUAGGUGGCCUCCTT340 GGAGGCCACCUACCGGAAAT 117 TGUUCCGGUAGGUGGCCUCTT 341GAGGCCACCUACCGGAACAT 118 TUGUUCCGGUAGGUGGCCUTT 342 AGGCCACCUACCGGAACAAT119 TCUCAGUCAUGUUCCGGUATT 343 UACCGGAACAUGACUGAGAT 120TGACGUGUGUCAUUAUCUGTT 344 CAGAUAAUGACACACGUCAT 121 TGGACGUGUGUCAUUAUCUTT345 AGAUAAUGACACACGUCCAT 122 TUGGACGUGUGUCAUUAUCTT 346GAUAAUGACACACGUCCAAT 123 TAUGGACGUGUGUCAUUAUTT 347 AUAAUGACACACGUCCAUAT124 TACCAUGGACGUGUGUCAUTT 348 AUGACACACGUCCAUGGUAT 125TAGUCCGCCCACCACGCGCTT 349 GCGCGUGGUGGGCGGACUAT 126 TUAGUCCGCCCACCACGCGTT350 CGCGUGGUGGGCGGACUAAT 127 TCUAGUCCGCCCACCACGCTT 351GCGUGGUGGGCGGACUAGAT 128 TACUAGUCCGCCCACCACGTT 352 CGUGGUGGGCGGACUAGUAT129 TCAGAGCCACUAGUCCGCCTT 353 GGCGGACUAGUGGCUCUGAT 130TGUUCCUCGGGCGCUGGCCTT 354 GGCCAGCGCCCGAGGAACAT 131 TAGUACCACUGUCAGUUCCTT355 GGAACUGACAGUGGUACUAT 132 TUCUUGACCAAGUACCACUTT 356AGUGGUACUUGGUCAAGAAT 133 TGAUCUUGACCAAGUACCATT 357 UGGUACUUGGUCAAGAUCAT134 TCGAUCUUGACCAAGUACCTT 358 GGUACUUGGUCAAGAUCGAT 135TGGCGAUCUUGACCAAGUATT 359 UACUUGGUCAAGAUCGCCAT 136 TUCGUGAAGGCGGUAGGAGTT360 CUCCUACCGCCUUCACGAAT 137 TCCUCGUGAAGGCGGUAGGTT 361CCUACCGCCUUCACGAGGAT 138 TCCCUCGUGAAGGCGGUAGTT 362 CUACCGCCUUCACGAGGGAT139 TCGCAGAGCACUGUCUCAGTT 363 CUGAGACAGUGCUCUGCGAT 140TCUUCAGCCCCCUCGAACUTT 364 AGUUCGAGGGGGCUGAAGAT 141 TUCUUCAGCCCCCUCGAACTT365 GUUCGAGGGGGCUGAAGAAT 142 TAUUCUUCAGCCCCCUCGATT 366UCGAGGGGGCUGAAGAAUAT 143 TUCUCCGUGCACGUUAGAGTT 367 CUCUAACGUGCACGGAGAAT144 TCGUCUCCGUGCACGUUAGTT 368 CUAACGUGCACGGAGACGAT 145TUGGCGUCUCCGUGCACGUTT 369 ACGUGCACGGAGACGCCAAT 146 ACUUUCACUUUCUUGGGCUTT370 UAUAGCCCAAGAAAGUGAAAGAT 147 AGGUCUUUCACUUUCUUGGTT 371AGCCCAAGAAAGUGAAAGUT 148 UGGUCUUUCACUUUCUUGGTT 372UAUGCCCAAGAAAGUGAAAGAAT 149 UGGUCUUUCACUUUCUUGGGCUC 373UAUCCCAAGAAAGUGAAAGACAT 150 TGGUCUUUCACUUUCUUGGGCUCUAU 374UAUCCAAGAAAGUGAAAGACCAT 151 TGGUCUUUCACUUUCUUGGGCUCUTT 375CCAAGAAAGUGAAAGACCUT 152 TGGUCUUUCACUUUCUUGGGCUCU 376UAUCAAGAAAGUGAAAGACCAAT 153 TGGUCUUUCACUUUCUUGGGCUC 377UAUUUUGAGCCUCAGCUUCUCAT 154 TCUUUCACUUUCUUGGGCUCCAA 378GCCCAAGAAAGUGAAAGACCAUAU 155 TUCUUUCACUUUCUUGGGCUCCA 379UAUAUGCCCAAGAAAGUGAAAGACCA 156 TGUCUUUCACUUUCUUGGGCUCC 380UGCCCAAGAAAGUGAAAGACCA 157 TUGGUCUUUCACUUUCUUGGGCU 381GCCCAAGAAAGUGAAAGACCA 158 TGAGAAGCUGAGGCUCAAAGCAC 382GGAGCCCAAGAAAGUGAAAGA 159 TGAGAAGCUGAGGCUCAAAGCACUAU 383GAGCCCAAGAAAGUGAAAGAA 160 TGGUCUUUCACUUUCUUGGGCAUAUA 384AGCCCAAGAAAGUGAAAGACA 161 TGGUCUUUCACUUUCUUGGGCUCAUAUA 385CCCAAGAAAGUGAAAGACCAA 162 TGAGAAGCUGAGGCUCAAAGCAUAUA 386GCUUUGAGCCUCAGCUUCUCA 163 TGAGAAGCUGAGGCUCAAAGCACAUAUA 387UAUAUGCUUUGAGCCUCAGCUUCUCA 164 TGGUCUUUCACUUUCUUGGGCUCUA 388UAUAUGAGCCCAAGAAAGUGAAAGACCA 165 TCACUUUCUUGGGCUCCAAACAGUAU 389UAUAUGUGCUUUGAGCCUCAGCUUCUCA 166 TUCACUUUCUUGGGCUCCAAACAUAU 390UAUAUGUUUGGAGCCCAAGAAAGUGA 167 TUUCACUUUCUUGGGCUCCAAACUAU 391UAUAUUUUGGAGCCCAAGAAAGUGAA 168 TUUUCACUUUCUUGGGCUCCAAAUAU 392UAUAUUUGGAGCCCAAGAAAGUGAAA 169 TAGCUGAGGCUCAAAGCACUUCUUAU 393UAUAUUGGAGCCCAAGAAAGUGAAAA 170 TGAAGCUGAGGCUCAAAGCACUUUAU 394UAUAUAAGUGCUUUGAGCCUCAGCUA 171 TUUGUUGCGGUCACCACAGCCCGUAU 395UAUAUGUGCUUUGAGCCUCAGCUUCA 172 TGCUUGUUGCGGUCACCACAGCCUAU 396UAUAUGGCUGUGGUGACCGCAACAAA 173 TGGCUUGUUGCGGUCACCACAGCUAU 397UAUAUCUGUGGUGACCGCAACAAGCA 174 TGGUCUUUCACUUUCUUGG 398UAUAUUGUGGUGACCGCAACAAGCCA 175 TGGUCUUUCACUUUCUUG 399UAUUAGCCCAAGAAAGUGAAAGACCA 176 TGGUCUUUCACUUUCUU 400UAUAAGCCCAAGAAAGUGAAAGACCA 177 UGGUCUUUCACUUUCUUGGGCUCUAU 401AUAUUGCCCAAGAAAGUGAAAGACCA 178 UGAAGCUGAGGCUCAAAGCACUUUAU 402CCAAGAAAGUGAAAGACCAUAU 179 UCACUUUCUUGGGCUCCA 403 UGGAGCCCAAGAAAGUGA 180UUCACUUUCUUGGGCUCC 404 GGAGCCCAAGAAAGUGAA 181 UUUCACUUUCUUGGGCUC 405GAGCCCAAGAAAGUGAAA 182 UUUUCACUUUCUUGGGCU 406 AGCCCAAGAAAGUGAAAA 183UCUUUCACUUUCUUGGGC 407 GCCCAAGAAAGUGAAAGA 184 UUCUUUCACUUUCUUGGG 408CCCAAGAAAGUGAAAGAA 185 UGUCUUUCACUUUCUUGG 409 CCAAGAAAGUGAAAGACA 186UGGUCUUUCACUUUCUUG 410 CAAGAAAGUGAAAGACCA 187 UUGGUCUUUCACUUUCUU 411AAGAAAGUGAAAGACCAA 188 UAGCUGAGGCUCAAAGCA 412 UGCUUUGAGCCUCAGCUA 189UGAAGCUGAGGCUCAAAG 413 CUUUGAGCCUCAGCUUCA 190 UGAGAAGCUGAGGCUCAA 414UUGAGCCUCAGCUUCUCA 191 UUUGUUGCGGUCACCACA 415 UGUGGUGACCGCAACAAA 192UCUUGUUGCGGUCACCAC 416 GUGGUGACCGCAACAAGA 193 UGCUUGUUGCGGUCACCA 417UGGUGACCGCAACAAGCA 194 UGGCUUGUUGCGGUCACC 418 GGUGACCGCAACAAGCCA 195UCACUUUCUUGGGCUCC 419 GGAGCCCAAGAAAGUGA 196 UUCACUUUCUUGGGCUC 420GAGCCCAAGAAAGUGAA 197 UUUCACUUUCUUGGGCU 421 AGCCCAAGAAAGUGAAA 198UUUUCACUUUCUUGGGC 422 GCCCAAGAAAGUGAAAA 199 UCUUUCACUUUCUUGGG 423CCCAAGAAAGUGAAAGA 200 UUCUUUCACUUUCUUGG 424 CCAAGAAAGUGAAAGAA 201UGUCUUUCACUUUCUUG 425 CAAGAAAGUGAAAGACA 202 UGGUCUUUCACUUUCUU 426AAGAAAGUGAAAGACCA 203 UUGGUCUUUCACUUUCU 427 AGAAAGUGAAAGACCAA 204UAGCUGAGGCUCAAAGC 428 GCUUUGAGCCUCAGCUA 205 UGAAGCUGAGGCUCAAA 429UUUGAGCCUCAGCUUCA 206 UGAGAAGCUGAGGCUCA 430 UGAGCCUCAGCUUCUCA 207UUUGUUGCGGUCACCAC 431 GUGGUGACCGCAACAAA 208 UCUUGUUGCGGUCACCA 432UGGUGACCGCAACAAGA 209 UGCUUGUUGCGGUCACC 433 GGUGACCGCAACAAGCA 210UGGCUUGUUGCGGUCAC 434 GUGACCGCAACAAGCCA 211 GGUCUUUCACUUUCUUGGGCUCUA 435AUAUGCCCAAGAAAGUGAAAGACCA 212 GUCUUUCACUUUCUUGGGCUCUA 436UAUGCCCAAGAAAGUGAAAGACCA 213 UCUUUCACUUUCUUGGGCUCUA 437AUGCCCAAGAAAGUGAAAGACCA 214 GGUCUUUCACUUUCUUGGGCUCUAU 438UAUAUGCCCAAGAAAGUGAAAGAUAU 215 GUCUUUCACUUUCUUGGGCUCUAU 439UAUAUGCCCAAGAAAGUGAAAGACC 216 UGGUCUUUCACUUUCUUGGGCTCUAU 440UAUGCCCAAGAAAGUGAAAGACCUAU 217 GGUCUUUCACUUUCUUGGGCUCU 441UAUGCCCAAGAAAGUGAAAGACCAAU 218 TGGUCUUUCACUUUCUUGGGCU 442UAUGCCCAAGAAAGUGAAAGACCAUU 219 GGUCUUUCACUUUCUUGGGCUC 443UAUGCCCAAGAAAGUGAAAGACCAUA 220 UAUGGUCUUUCACUUUCUUGGGCUCU 444UUAGAGCCCAAGAAAGUGAAAGACCA 221 TGGUCUUUCACUUUCUUGGGC 445UUAUUGCCCAAGAAAGUGAAAGACCA 222 UGGUCUUUCACUUUCUUGGGCUUCAU 446UUGAUGCCCAAGAAAGUGAAAGACCA 223 UUAUGGUCUUUCACUUUCUUGGGCUC 447UAUGAGCCCAAGAAAGUGAAAGACCA 224 UGAUGGUCUUUCACUUUCUUGGGCUC 448AUAGAGCCCAAGAAAGUGAAAGACCA 1307 UGGUCUUUCACUUUCUUGGGCUAUAU 449AUGCCCAAGAAAGUGAAAGACCUAUU 1308 UCUUUCACUUUCUUGGG 450AUGCCCAAGAAAGUGAAAGACCUGAU 1309 ACUUUCACUUUCUUGGG 1317ATAGAGCCCAAGAAAGUGAAAGACCA 1310 UGGUCUUUCACUUUCUUGGGCAUUAU 1318CCCAAGAAAGUGAAAGU 1311 UGGUCUUUCACUUUCUUGGGCUCAUA 1319GAGCCCAAGAAAGUGAAAGACCUAUU 1312 AGGUCUUUCACUUUCUUGGGCUCUAU 1320GAGCCCAAGAAAGUGAAAGACCUGAU 1313 GGUCUUUCACUUUCUUGGGCUCUAU 1321UAUAUGCCCAAGAAAGUGAAAGACCU 1314 UCGUCUUUCACUUUCUUGGGCUCUAU 1315UAGUCUUUCACUUUCUUGGGCUCUAU 1316 UUGUCUUUCACUUUCUUGGGCUCUAU 1407GGGUGGUAGCACACCAGGG 1375 CCCUGGUGUGCUACCACCC 1408 GGGGUGGUAGCACACCAGG1376 CCUGGUGUGCUACCACCCC 1409 GGGGGUGGUAGCACACCAG 1377CUGGUGUGCUACCACCCCC 1410 UCACUUUCUUGGGCUCCAA 1378 UUGGAGCCCAAGAAAGUGA1411 UUCACUUUCUUGGGCUCCA 1379 UGGAGCCCAAGAAAGUGAA 1412UUUCACUUUCUUGGGCUCC 1380 GGAGCCCAAGAAAGUGAAA 1413 CUUUCACUUUCUUGGGCUC1381 GAGCCCAAGAAAGUGAAAG 1414 UCUUUCACUUUCUUGGGCU 1382AGCCCAAGAAAGUGAAAGA 1415 GUCUUUCACUUUCUUGGGC 1383 GCCCAAGAAAGUGAAAGAC1416 GGUCUUUCACUUUCUUGGG 1384 CCCAAGAAAGUGAAAGACC 1417UGGUCUUUCACUUUCUUGG 1385 CCAAGAAAGUGAAAGACCA 1418 GUGGUCUUUCACUUUCUUG1386 CAAGAAAGUGAAAGACCAC 1419 AAGCUGAGGCUCAAAGCAC 1387GUGCUUUGAGCCUCAGCUU 1420 GAAGCUGAGGCUCAAAGCA 1388 UGCUUUGAGCCUCAGCUUC1421 AGAAGCUGAGGCUCAAAGC 1389 GCUUUGAGCCUCAGCUUCU 1422GGAGAAGCUGAGGCUCAAA 1390 UUUGAGCCUCAGCUUCUCC 1423 GGCAGGCCUGGCUGGCCAG1391 CUGGCCAGCCAGGCCUGCC 1424 CGCCCCCUCGAACUGGUGG 1392CCACCAGUUCGAGGGGGCG 1425 GUUGCGGUCACCACAGCCC 1393 GGGCUGUGGUGACCGCAAC1426 UGUUGCGGUCACCACAGCC 1394 GGCUGUGGUGACCGCAACA 1427UUGUUGCGGUCACCACAGC 1395 GCUGUGGUGACCGCAACAA 1428 CUUGUUGCGGUCACCACAG1396 CUGUGGUGACCGCAACAAG 1429 GCUUGUUGCGGUCACCACA 1397UGUGGUGACCGCAACAAGC 1430 GGCUUGUUGCGGUCACCAC 1398 GUGGUGACCGCAACAAGCC1431 UGGCUUGUUGCGGUCACCA 1399 UGGUGACCGCAACAAGCCA 1432AAAGCACUUUAUUGAGUUC 1400 GAACUCAAUAAAGUGCUUU 1433 CAAAGCACUUUAUUGAGUU1401 AACUCAAUAAAGUGCUUUG 1434 UCAAAGCACUUUAUUGAGU 1402ACUCAAUAAAGUGCUUUGA 1435 UUCAAAGCACUUUAUUGAG 1403 CUCAAUAAAGUGCUUUGAA1436 UUUCAAAGCACUUUAUUGA 1404 UCAAUAAAGUGCUUUGAAA 1437UUUUCAAAGCACUUUAUUG 1405 CAAUAAAGUGCUUUGAAAA 1438 AUUUUCAAAGCACUUUAUU1406 AAUAAAGUGCUUUGAAAAU 1463 TGGUGGUAGCACACCAGGGTT 1439CCCUGGUGUGCUACCACCAT 1464 TGGGUGGUAGCACACCAGGTT 1440CCUGGUGUGCUACCACCCAT 1465 TGGGGUGGUAGCACACCAGTT 1441CUGGUGUGCUACCACCCCAT 1466 TCACUUUCUUGGGCUCCAATT 1442UUGGAGCCCAAGAAAGUGAT 1467 TUCACUUUCUUGGGCUCCATT 1443UGGAGCCCAAGAAAGUGAAT 1468 TUUCACUUUCUUGGGCUCCTT 1444GGAGCCCAAGAAAGUGAAAT 1469 TUUUCACUUUCUUGGGCUCTT 1445GAGCCCAAGAAAGUGAAAAT 1470 TAGCUGAGGCUCAAAGCACTT 1446GCCCAAGAAAGUGAAAGAAT 1471 TAAGCUGAGGCUCAAAGCATT 1447GUGCUUUGAGCCUCAGCUAT 1472 TGAAGCUGAGGCUCAAAGCTT 1448UGCUUUGAGCCUCAGCUUAT 1473 TGCAGGCCUGGCUGGCCAGTT 1449GCUUUGAGCCUCAGCUUCAT 1474 TGCCCCCUCGAACUGGUGGTT 1450CUGGCCAGCCAGGCCUGCAT 1475 TUUGCGGUCACCACAGCCCTT 1451CCACCAGUUCGAGGGGGCAT 1476 TGUUGCGGUCACCACAGCCTT 1452GGGCUGUGGUGACCGCAAAT 1477 TUGUUGCGGUCACCACAGCTT 1453GGCUGUGGUGACCGCAACAT 1478 TUUGUUGCGGUCACCACAGTT 1454GCUGUGGUGACCGCAACAAT 1479 TCUUGUUGCGGUCACCACATT 1455CUGUGGUGACCGCAACAAAT 1480 TGCUUGUUGCGGUCACCACTT 1456UGUGGUGACCGCAACAAGAT 1481 TGGCUUGUUGCGGUCACCATT 1457GUGGUGACCGCAACAAGCAT 1482 TAAGCACUUUAUUGAGUUCTT 1458UGGUGACCGCAACAAGCCAT 1483 TAAAGCACUUUAUUGAGUUTT 1459GAACUCAAUAAAGUGCUUAT 1484 TCAAAGCACUUUAUUGAGUTT 1460CUCAAUAAAGUGCUUUGAAT 1485 TUCAAAGCACUUUAUUGAGTT 1461UCAAUAAAGUGCUUUGAAAT 1486 TUUCAAAGCACUUUAUUGATT 1462CAAUAAAGUGCUUUGAAAAT 1487 TUUUCAAAGCACUUUAUUGTT 1488TUUUUCAAAGCACUUUAUUTT 1602 AUCGAAAGUGUUGACUCCA 1489 UGGAGUCAACACUUUCGAU1603 AAUCGAAAGUGUUGACUCC 1490 GGAGUCAACACUUUCGAUU 1604UGUACUUAUGCUCCUUGGG 1491 CCCAAGGAGCAUAAGUACA 1605 UUGUACUUAUGCUCCUUGG1492 CCAAGGAGCAUAAGUACAA 1606 UUUGUACUUAUGCUCCUUG 1493CAAGGAGCAUAAGUACAAA 1607 UCAGCUUUGUACUUAUGCU 1494 AGCAUAAGUACAAAGCUGA1608 AACGACUGUGUGCUCUUCA 1495 UGAAGAGCACACAGUCGUU 1609GAACGACUGUGUGCUCUUC 1496 GAAGAGCACACAGUCGUUC 1610 AGAACGACUGUGUGCUCUU1497 AAGAGCACACAGUCGUUCU 1611 GACAGUGAGAACGACUGUG 1498CACAGUCGUUCUCACUGUC 1612 GUGACAGUGAGAACGACUG 1499 CAGUCGUUCUCACUGUCAC1613 GGUACAUUUGUGGUACAGC 1500 GCUGUACCACAAAUGUACC 1614GGGUACAUUUGUGGUACAG 1501 CUGUACCACAAAUGUACCC 1615 UGGGUACAUUUGUGGUACA1502 UGUACCACAAAUGUACCCA 1616 CUUGUGGGUACAUUUGUGG 1503CCACAAAUGUACCCACAAG 1617 GACCCUUGCACUGGCAUCU 1504 AGAUGCCAGUGCAAGGGUC1618 ACCUCUAGGCAGCGACCCC 1505 GGGGUCGCUGCCUAGAGGU 1619CCGCGGCCAUCAUAGCAGC 1506 GCUGCUAUGAUGGCCGCGG 1620 CCCGCGGCCAUCAUAGCAG1507 CUGCUAUGAUGGCCGCGGG 1621 GUAGCUGAGCCCGCGGCCA 1508UGGCCGCGGGCUCAGCUAC 1622 GCGGUAGCUGAGCCCGCGG 1509 CCGCGGGCUCAGCUACCGC1623 CGCACCCGAGAGCGUGGUC 1510 GACCACGCUCUCGGGUGCG 1624GCGCACCCGAGAGCGUGGU 1511 ACCACGCUCUCGGGUGCGC 1625 GGCGCACCCGAGAGCGUGG1512 CCACGCUCUCGGGUGCGCC 1626 AGUCCCCAGUUCCGCGCUU 1513AAGCGCGGAACUGGGGACU 1627 AGGCGUGGCCGCCCAGUCC 1514 GGACUGGGCGGCCACGCCU1628 UCGUUGUCCGGGUUCCGGC 1515 GCCGGAACCCGGACAACGA 1629UGUCGUUGUCCGGGUUCCG 1516 CGGAACCCGGACAACGACA 1630 AUGUCGUUGUCCGGGUUCC1517 GGAACCCGGACAACGACAU 1631 GAUGUCGUUGUCCGGGUUC 1518GAACCCGGACAACGACAUC 1632 GGCGGAUGUCGUUGUCCGG 1519 CCGGACAACGACAUCCGCC1633 CACGGGCGGAUGUCGUUGU 1520 ACAACGACAUCCGCCCGUG 1634CCACGGGCGGAUGUCGUUG 1521 CAACGACAUCCGCCCGUGG 1635 ACCACGGGCGGAUGUCGUU1522 AACGACAUCCGCCCGUGGU 1636 CACCACGGGCGGAUGUCGU 1523ACGACAUCCGCCCGUGGUG 1637 GAAGCACCACGGGCGGAUG 1524 CAUCCGCCCGUGGUGCUUC1638 CGAAGCACCACGGGCGGAU 1525 AUCCGCCCGUGGUGCUUCG 1639CACGAAGCACCACGGGCGG 1526 CCGCCCGUGGUGCUUCGUG 1640 AGCACGAAGCACCACGGGC1527 GCCCGUGGUGCUUCGUGCU 1641 GCAUGAGUGGGACAUGAAG 1528CUUCAUGUCCCACUCAUGC 1642 CUUCGGCGGUGCCGGCUGC 1529 GCAGCCGGCACCGCCGAAG1643 GACAGACUCUUGCGGAGCC 1530 GGCUCCGCAAGAGUCUGUC 1644AGACAGACUCUUGCGGAGC 1531 GCUCCGCAAGAGUCUGUCU 1645 GGUCAUCGAAGACAGACUC1532 GAGUCUGUCUUCGAUGACC 1646 GGGUCAUCGAAGACAGACU 1533AGUCUGUCUUCGAUGACCC 1647 GACGCGGGUCAUCGAAGAC 1534 GUCUUCGAUGACCCGCGUC1648 CGACGCGGGUCAUCGAAGA 1535 UCUUCGAUGACCCGCGUCG 1649ACGACGCGGGUCAUCGAAG 1536 CUUCGAUGACCCGCGUCGU 1650 AACGACGCGGGUCAUCGAA1537 UUCGAUGACCCGCGUCGUU 1651 CAACGACGCGGGUCAUCGA 1538UCGAUGACCCGCGUCGUUG 1652 CCAACGACGCGGGUCAUCG 1539 CGAUGACCCGCGUCGUUGG1653 GCCAACGACGCGGGUCAUC 1540 GAUGACCCGCGUCGUUGGC 1654CCGCCAACGACGCGGGUCA 1541 UGACCCGCGUCGUUGGCGG 1655 CCCGCCAACGACGCGGGUC1542 GACCCGCGUCGUUGGCGGG 1656 CCCGCGUAGCGCCACCAGC 1543GCUGGUGGCGCUACGCGGG 1657 GCCCCGCGUAGCGCCACCA 1544 UGGUGGCGCUACGCGGGGC1658 CGCCCCGCGUAGCGCCACC 1545 GGUGGCGCUACGCGGGGCG 1659GCGCCCCGCGUAGCGCCAC 1546 GUGGCGCUACGCGGGGCGC 1660 GGGGUGCGCCCCGCGUAGC1547 GCUACGCGGGGCGCACCCC 1661 GGCGAUGUAGGGGUGCGCC 1548GGCGCACCCCUACAUCGCC 1662 GCGCGGCGAUGUAGGGGUG 1549 CACCCCUACAUCGCCGCGC1663 CAGCGCGGCGAUGUAGGGG 1550 CCCCUACAUCGCCGCGCUG 1664ACAGCGCGGCGAUGUAGGG 1551 CCCUACAUCGCCGCGCUGU 1665 UACAGCGCGGCGAUGUAGG1552 CCUACAUCGCCGCGCUGUA 1666 GUACAGCGCGGCGAUGUAG 1553CUACAUCGCCGCGCUGUAC 1667 AGUACAGCGCGGCGAUGUA 1554 UACAUCGCCGCGCUGUACU1668 CCAGUACAGCGCGGCGAUG 1555 CAUCGCCGCGCUGUACUGG 1669CCCCAGUACAGCGCGGCGA 1556 UCGCCGCGCUGUACUGGGG 1670 GAUGAGGCUGCCGGCGCAG1557 CUGCGCCGGCAGCCUCAUC 1671 CCGUCAGAUCCUCGGGUGC 1558GCACCCGAGGAUCUGACGG 1672 ACCGUCAGAUCCUCGGGUG 1559 CACCCGAGGAUCUGACGGU1673 GCGAGAAGGCCUCGUGCAA 1560 UUGCACGAGGCCUUCUCGC 1674GGCGAGAAGGCCUCGUGCA 1561 UGCACGAGGCCUUCUCGCC 1675 CAACAGAGCCAGGUCGUGC1562 GCACGACCUGGCUCUGUUG 1676 CCUGAAGGCGCAACAGAGC 1563GCUCUGUUGCGCCUUCAGG 1677 CAUCCUCCUGAAGGCGCAA 1564 UUGCGCCUUCAGGAGGAUG1678 GAGCGCGCAGCUGCCGUCC 1565 GGACGGCAGCUGCGCGCUC 1679GUAAGGCGACAGGAGCGCG 1566 CGCGCUCCUGUCGCCUUAC 1680 CGUAAGGCGACAGGAGCGC1567 GCGCUCCUGUCGCCUUACG 1681 ACGUAAGGCGACAGGAGCG 1568CGCUCCUGUCGCCUUACGU 1682 AACGUAAGGCGACAGGAGC 1569 GCUCCUGUCGCCUUACGUU1683 GAACGUAAGGCGACAGGAG 1570 CUCCUGUCGCCUUACGUUC 1684UGAACGUAAGGCGACAGGA 1571 UCCUGUCGCCUUACGUUCA 1685 GGCUGAACGUAAGGCGACA1572 UGUCGCCUUACGUUCAGCC 1686 CGGCUGAACGUAAGGCGAC 1573GUCGCCUUACGUUCAGCCG 1687 CCGGCUGAACGUAAGGCGA 1574 UCGCCUUACGUUCAGCCGG1688 ACCGGCUGAACGUAAGGCG 1575 CGCCUUACGUUCAGCCGGU 1689CACCGGCUGAACGUAAGGC 1576 GCCUUACGUUCAGCCGGUG 1690 CACACCGGCUGAACGUAAG1577 CUUACGUUCAGCCGGUGUG 1691 AGGCACACCGGCUGAACGU 1578ACGUUCAGCCGGUGUGCCU 1692 GCCGCUUGGCAGGCACACC 1579 GGUGUGCCUGCCAAGCGGC1693 GCCCCCUCGAACUGGUGGC 1580 GCCACCAGUUCGAGGGGGC 1694CCGCCCCCUCGAACUGGUG 1581 CACCAGUUCGAGGGGGCGG 1695 UAUUCCUCCGCCCCCUCGA1582 UCGAGGGGGCGGAGGAAUA 1696 CUCGAGGAACCCUGCGCAG 1583CUGCGCAGGGUUCCUCGAG 1697 CCUCGAGGAACCCUGCGCA 1584 UGCGCAGGGUUCCUCGAGG1698 CCCUCGAGGAACCCUGCGC 1585 GCGCAGGGUUCCUCGAGGG 1699CGGUGCCGCCCUCGAGGAA 1586 UUCCUCGAGGGCGGCACCG 1700 CAUCGGUGCCGCCCUCGAG1587 CUCGAGGGCGGCACCGAUG 1701 GCAUCGGUGCCGCCCUCGA 1588UCGAGGGCGGCACCGAUGC 1702 AGGGUGAGCCGGCGCUCUG 1589 CAGAGCGCCGGCUCACCCU1703 AGCCCGAUCCCCAGCUGAU 1590 AUCAGCUGGGGAUCGGGCU 1704CGGUCACCACAGCCCGAUC 1591 GAUCGGGCUGUGGUGACCG 1705 GACGCCUGGCUUGUUGCGG1592 CCGCAACAAGCCAGGCGUC 1706 UAGACGCCUGGCUUGUUGC 1593GCAACAAGCCAGGCGUCUA 1707 CACAUCGGUGUAGACGCCU 1594 AGGCGUCUACACCGAUGUG1708 CCACAUCGGUGUAGACGCC 1595 GGCGUCUACACCGAUGUGG 1709GCCACAUCGGUGUAGACGC 1596 GCGUCUACACCGAUGUGGC 1710 GGUGUGCUCCCGGAUCCAG1597 CUGGAUCCGGGAGCACACC 1711 UGAGUCCCUGAGCAAUCAG 1598CUGAUUGCUCAGGGACUCA 1712 AGAUGAGUCCCUGAGCAAU 1599 AUUGCUCAGGGACUCAUCU1713 AGCACUUUAUUGAGUUCCU 1600 AGGAACUCAAUAAAGUGCU 1714AAGCACUUUAUUGAGUUCC 1601 GGAACUCAAUAAAGUGCUU 1827 TUCGAAAGUGUUGACUCCATT1715 UGGAGUCAACACUUUCGAAT 1828 TAUCGAAAGUGUUGACUCCTT 1716GGAGUCAACACUUUCGAUAT 1829 TGUACUUAUGCUCCUUGGGTT 1717CCCAAGGAGCAUAAGUACAT 1830 TUGUACUUAUGCUCCUUGGTT 1718CCAAGGAGCAUAAGUACAAT 1831 TUUGUACUUAUGCUCCUUGTT 1719CAAGGAGCAUAAGUACAAAT 1832 TCAGCUUUGUACUUAUGCUTT 1720AGCAUAAGUACAAAGCUGAT 1833 TACGACUGUGUGCUCUUCATT 1721UGAAGAGCACACAGUCGUAT 1834 TAACGACUGUGUGCUCUUCTT 1722GAAGAGCACACAGUCGUUAT 1835 TGAACGACUGUGUGCUCUUTT 1723AAGAGCACACAGUCGUUCAT 1836 TACAGUGAGAACGACUGUGTT 1724CACAGUCGUUCUCACUGUAT 1837 TUGACAGUGAGAACGACUGTT 1725CAGUCGUUCUCACUGUCAAT 1838 TGUACAUUUGUGGUACAGCTT 1726GCUGUACCACAAAUGUACAT 1839 TGGUACAUUUGUGGUACAGTT 1727CUGUACCACAAAUGUACCAT 1840 TGGGUACAUUUGUGGUACATT 1728UGUACCACAAAUGUACCCAT 1841 TUUGUGGGUACAUUUGUGGTT 1729CCACAAAUGUACCCACAAAT 1842 TACCCUUGCACUGGCAUCUTT 1730AGAUGCCAGUGCAAGGGUAT 1843 TCCUCUAGGCAGCGACCCCTT 1731GGGGUCGCUGCCUAGAGGAT 1844 TCGCGGCCAUCAUAGCAGCTT 1732GCUGCUAUGAUGGCCGCGAT 1845 TCCGCGGCCAUCAUAGCAGTT 1733CUGCUAUGAUGGCCGCGGAT 1846 TUAGCUGAGCCCGCGGCCATT 1734UGGCCGCGGGCUCAGCUAAT 1847 TCGGUAGCUGAGCCCGCGGTT 1735CCGCGGGCUCAGCUACCGAT 1848 TGCACCCGAGAGCGUGGUCTT 1736GACCACGCUCUCGGGUGCAT 1849 TCGCACCCGAGAGCGUGGUTT 1737ACCACGCUCUCGGGUGCGAT 1850 TGCGCACCCGAGAGCGUGGTT 1738CCACGCUCUCGGGUGCGCAT 1851 TGUCCCCAGUUCCGCGCUUTT 1739GGACUGGGCGGCCACGCCAT 1852 TGGCGUGGCCGCCCAGUCCTT 1740GCCGGAACCCGGACAACGAT 1853 TCGUUGUCCGGGUUCCGGCTT 1741CGGAACCCGGACAACGACAT 1854 TGUCGUUGUCCGGGUUCCGTT 1742GGAACCCGGACAACGACAAT 1855 TUGUCGUUGUCCGGGUUCCTT 1743GAACCCGGACAACGACAUAT 1856 TAUGUCGUUGUCCGGGUUCTT 1744CCGGACAACGACAUCCGCAT 1857 TGCGGAUGUCGUUGUCCGGTT 1745ACAACGACAUCCGCCCGUAT 1858 TACGGGCGGAUGUCGUUGUTT 1746CAACGACAUCCGCCCGUGAT 1859 TCACGGGCGGAUGUCGUUGTT 1747AACGACAUCCGCCCGUGGAT 1860 TCCACGGGCGGAUGUCGUUTT 1748ACGACAUCCGCCCGUGGUAT 1861 TACCACGGGCGGAUGUCGUTT 1749CAUCCGCCCGUGGUGCUUAT 1862 TAAGCACCACGGGCGGAUGTT 1750AUCCGCCCGUGGUGCUUCAT 1863 TGAAGCACCACGGGCGGAUTT 1751CCGCCCGUGGUGCUUCGUAT 1864 TACGAAGCACCACGGGCGGTT 1752GCCCGUGGUGCUUCGUGCAT 1865 TGCACGAAGCACCACGGGCTT 1753CUUCAUGUCCCACUCAUGAT 1866 TCAUGAGUGGGACAUGAAGTT 1754GCAGCCGGCACCGCCGAAAT 1867 TUUCGGCGGUGCCGGCUGCTT 1755GGCUCCGCAAGAGUCUGUAT 1868 TACAGACUCUUGCGGAGCCTT 1756GCUCCGCAAGAGUCUGUCAT 1869 TGACAGACUCUUGCGGAGCTT 1757GAGUCUGUCUUCGAUGACAT 1870 TGUCAUCGAAGACAGACUCTT 1758AGUCUGUCUUCGAUGACCAT 1871 TGGUCAUCGAAGACAGACUTT 1759GUCUUCGAUGACCCGCGUAT 1872 TACGCGGGUCAUCGAAGACTT 1760UCUUCGAUGACCCGCGUCAT 1873 TGACGCGGGUCAUCGAAGATT 1761CUUCGAUGACCCGCGUCGAT 1874 TCGACGCGGGUCAUCGAAGTT 1762UUCGAUGACCCGCGUCGUAT 1875 TACGACGCGGGUCAUCGAATT 1763UCGAUGACCCGCGUCGUUAT 1876 TAACGACGCGGGUCAUCGATT 1764CGAUGACCCGCGUCGUUGAT 1877 TCAACGACGCGGGUCAUCGTT 1765GAUGACCCGCGUCGUUGGAT 1878 TCCAACGACGCGGGUCAUCTT 1766UGACCCGCGUCGUUGGCGAT 1879 TCGCCAACGACGCGGGUCATT 1767GACCCGCGUCGUUGGCGGAT 1880 TCCGCCAACGACGCGGGUCTT 1768GCUGGUGGCGCUACGCGGAT 1881 TCCGCGUAGCGCCACCAGCTT 1769UGGUGGCGCUACGCGGGGAT 1882 TCCCCGCGUAGCGCCACCATT 1770GGUGGCGCUACGCGGGGCAT 1883 TGCCCCGCGUAGCGCCACCTT 1771GUGGCGCUACGCGGGGCGAT 1884 TCGCCCCGCGUAGCGCCACTT 1772GCUACGCGGGGCGCACCCAT 1885 TGGGUGCGCCCCGCGUAGCTT 1773GGCGCACCCCUACAUCGCAT 1886 TGCGAUGUAGGGGUGCGCCTT 1774CACCCCUACAUCGCCGCGAT 1887 TCGCGGCGAUGUAGGGGUGTT 1775CCCCUACAUCGCCGCGCUAT 1888 TAGCGCGGCGAUGUAGGGGTT 1776CCCUACAUCGCCGCGCUGAT 1889 TCAGCGCGGCGAUGUAGGGTT 1777CCUACAUCGCCGCGCUGUAT 1890 TACAGCGCGGCGAUGUAGGTT 1778CUACAUCGCCGCGCUGUAAT 1891 TUACAGCGCGGCGAUGUAGTT 1779UACAUCGCCGCGCUGUACAT 1892 TGUACAGCGCGGCGAUGUATT 1780CAUCGCCGCGCUGUACUGAT 1893 TCAGUACAGCGCGGCGAUGTT 1781UCGCCGCGCUGUACUGGGAT 1894 TCCCAGUACAGCGCGGCGATT 1782CUGCGCCGGCAGCCUCAUAT 1895 TAUGAGGCUGCCGGCGCAGTT 1783GCACCCGAGGAUCUGACGAT 1896 TCGUCAGAUCCUCGGGUGCTT 1784CACCCGAGGAUCUGACGGAT 1897 TCCGUCAGAUCCUCGGGUGTT 1785UUGCACGAGGCCUUCUCGAT 1898 TCGAGAAGGCCUCGUGCAATT 1786UGCACGAGGCCUUCUCGCAT 1899 TGCGAGAAGGCCUCGUGCATT 1787GCACGACCUGGCUCUGUUAT 1900 TAACAGAGCCAGGUCGUGCTT 1788GCUCUGUUGCGCCUUCAGAT 1901 TCUGAAGGCGCAACAGAGCTT 1789UUGCGCCUUCAGGAGGAUAT 1902 TAUCCUCCUGAAGGCGCAATT 1790GGACGGCAGCUGCGCGCUAT 1903 TAGCGCGCAGCUGCCGUCCTT 1791CGCGCUCCUGUCGCCUUAAT 1904 TUAAGGCGACAGGAGCGCGTT 1792GCGCUCCUGUCGCCUUACAT 1905 TGUAAGGCGACAGGAGCGCTT 1793CGCUCCUGUCGCCUUACGAT 1906 TCGUAAGGCGACAGGAGCGTT 1794GCUCCUGUCGCCUUACGUAT 1907 TACGUAAGGCGACAGGAGCTT 1795CUCCUGUCGCCUUACGUUAT 1908 TAACGUAAGGCGACAGGAGTT 1796UCCUGUCGCCUUACGUUCAT 1909 TGAACGUAAGGCGACAGGATT 1797UGUCGCCUUACGUUCAGCAT 1910 TGCUGAACGUAAGGCGACATT 1798GUCGCCUUACGUUCAGCCAT 1911 TGGCUGAACGUAAGGCGACTT 1799UCGCCUUACGUUCAGCCGAT 1912 TCGGCUGAACGUAAGGCGATT 1800CGCCUUACGUUCAGCCGGAT 1913 TCCGGCUGAACGUAAGGCGTT 1801GCCUUACGUUCAGCCGGUAT 1914 TACCGGCUGAACGUAAGGCTT 1802CUUACGUUCAGCCGGUGUAT 1915 TACACCGGCUGAACGUAAGTT 1803ACGUUCAGCCGGUGUGCCAT 1916 TGGCACACCGGCUGAACGUTT 1804GGUGUGCCUGCCAAGCGGAT 1917 TCCGCUUGGCAGGCACACCTT 1805GCCACCAGUUCGAGGGGGAT 1918 TCCCCCUCGAACUGGUGGCTT 1806CACCAGUUCGAGGGGGCGAT 1919 TCGCCCCCUCGAACUGGUGTT 1807UCGAGGGGGCGGAGGAAUAT 1920 TAUUCCUCCGCCCCCUCGATT 1808CUGCGCAGGGUUCCUCGAAT 1921 TUCGAGGAACCCUGCGCAGTT 1809UGCGCAGGGUUCCUCGAGAT 1922 TCUCGAGGAACCCUGCGCATT 1810GCGCAGGGUUCCUCGAGGAT 1923 TCCUCGAGGAACCCUGCGCTT 1811UUCCUCGAGGGCGGCACCAT 1924 TGGUGCCGCCCUCGAGGAATT 1812CUCGAGGGCGGCACCGAUAT 1925 TAUCGGUGCCGCCCUCGAGTT 1813UCGAGGGCGGCACCGAUGAT 1926 TCAUCGGUGCCGCCCUCGATT 1814CAGAGCGCCGGCUCACCCAT 1927 TGGGUGAGCCGGCGCUCUGTT 1815AUCAGCUGGGGAUCGGGCAT 1928 TGCCCGAUCCCCAGCUGAUTT 1816GAUCGGGCUGUGGUGACCAT 1929 TGGUCACCACAGCCCGAUCTT 1817CCGCAACAAGCCAGGCGUAT 1930 TACGCCUGGCUUGUUGCGGTT 1818GCAACAAGCCAGGCGUCUAT 1931 TAGACGCCUGGCUUGUUGCTT 1819AGGCGUCUACACCGAUGUAT 1932 TACAUCGGUGUAGACGCCUTT 1820GGCGUCUACACCGAUGUGAT 1933 TCACAUCGGUGUAGACGCCTT 1821GCGUCUACACCGAUGUGGAT 1934 TCCACAUCGGUGUAGACGCTT 1822CUGGAUCCGGGAGCACACAT 1935 TGUGUGCUCCCGGAUCCAGTT 1823CUGAUUGCUCAGGGACUCAT 1936 TGAGUCCCUGAGCAAUCAGTT 1824AUUGCUCAGGGACUCAUCAT 1937 TGAUGAGUCCCUGAGCAAUTT 1825AGGAACUCAAUAAAGUGCAT 1938 TGCACUUUAUUGAGUUCCUTT 1826GGAACUCAAUAAAGUGCUAT 1939 TAGCACUUUAUUGAGUUCCTT 2172GGUCUUUCACUUUCUUGGGCUC 2166 GCCCAAGAAAGUGAAAGACC 2173GAGAAGCUGAGGCUCAAAGCAC 2167 GCUUUGAGCCUCAGCUUCUC 2174GUCUUUCACUUUCUUGGGCUCC 2168 AGCCCAAGAAAGUGAAAGAC 2175CUUUCACUUUCUUGGGCUCCAA 2169 GGAGCCCAAGAAAGUGAAAG 2176UCUUUCACUUUCUUGGGCUCCA 2170 GAGCCCAAGAAAGUGAAAGA 2177UGGUCUUUCACUUUCUUGGGCU 2171 CCCAAGAAAGUGAAAGACCA 2178UGGUCUUUCACUUUCUUGGGCUCAGU 2183 GACAUGCCCAAGAAAGUGAAAGACCA 2179UGGUCUUUCACUUUCUUGGGCUCCAA 2184 GCGAUGCCCAAGAAAGUGAAAGACCA 2180UGGUCUUUCACUUUCUUGGGCUCCAG 2185 UGAAUGCCCAAGAAAGUGAAAGACCA 2181UGGUCUUUCACUUUCUUGGGCUCGCG 2186 UUGGAGCCCAAGAAAGUGAAAGACCA 2182UGGUCUUUCACUUUCUUGGGCUCUAT

The F12 RNAi triggers described herein are formed by annealing anantisense strand with a sense strand. In some embodiments, an F12 RNAitrigger antisense strand comprises a nucleotide sequence of any of thesequences in Tables 1 and 2. In some embodiments, an F12 RNAi triggerantisense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18,2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24,2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Tables 1 and2. In some embodiments, an F12 RNAi trigger sense strand comprises thenucleotide sequence of any of the sequences in Tables 1 and 3. In someembodiments, an F12 RNAi trigger sense strand comprises the sequence ofnucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21,1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any ofthe sequences in Tables 1 and 3.

In some embodiments, the sense and antisense strands of the RNAitriggers described herein contain the same number of nucleotides. Insome embodiments the sense and antisense strands of the RNAi triggersdescribed herein contain different numbers of nucleotides. In someembodiments, the sense strand 5′ end and the antisense strand 3′ end ofa herein described RNAi trigger form a blunt end. In some embodiments,the sense strand 3′ end and the antisense strand 5′ end of a hereindescribed RNAi trigger form a blunt end. In some embodiments, both endsof a herein described RNAi trigger form a blunt end. In someembodiments, neither end of a herein described RNAi trigger isblunt-ended. As used herein a blunt end refers to an end of a doublestranded trigger molecule in which the terminal nucleotides of the twoannealed strands are complementary (form a complementary base-pair). Insome embodiments, the sense strand 5′ end and the antisense strand 3′end of a herein described RNAi trigger form a frayed end. In someembodiments, the sense strand 3′ end and the antisense strand 5′ end ofa herein described RNAi trigger form a frayed end. In some embodiments,both ends of a herein described RNAi trigger form a frayed end. In someembodiments, neither end of a herein described RNAi trigger is a frayedend. As used herein a frayed end refers to an end of a double strandedtrigger molecule in which the terminal nucleotides of the two annealedstrands from a pair (i.e. do not form an overhang) but are notcomplementary (i.e. form a non-complementary pair). As used herein, anoverhang is a stretch of one or more unpaired nucleotides at the end ofone strand of a double stranded RNAi trigger molecule. The unpairednucleotides may be on the sense strand or the antisense strand, creatingeither 3′ or 5′ overhangs. In some embodiments the RNAi trigger moleculecontains: a blunt end and a frayed end, a blunt end and 5′ overhang end,a blunt end and a 3′ overhang end, a frayed end and a 5′ overhand end, afrayed end and a 3′ overhang end, two 5′ overhang ends, two 3′ overhangends, a 5′ overhang end and a 3′ overhand end, two frayed ends, or twoblunt ends.

In some embodiments, an F12 RNAi trigger contains one or more modifiednucleotides. A nucleotide base (or nucleobase) is a heterocyclicpyrimidine or purine compound which is a constituent of all nucleicacids and includes adenine (A), guanine (G), cytosine (C), thymine (T),and uracil (U). As used herein, “G”, “g”, “C”, “c”, “A”, “a”, “U”, “u”,and “T”, each generally stand for a nucleobase, nucleoside, nucleotideor nucleotide mimic that contains guanine, cytosine, adenine, uracil andthymidine as a base, respectively. Also as used herein, the term“nucleotide” can include a modified nucleotide or nucleotide mimic,abasic site, or a surrogate replacement moiety. As used herein, a“modified nucleotide” is a nucleotide, deoxynucleotide, nucleotidemimic, abasic site, or a surrogate replacement moiety other than aribonucleotide (2′-hydroxyl nucleotide). In some embodiments, a modifiednucleotide comprises a 2′-modified nucleotide (i.e. a nucleotide with agroup other than a hydroxyl group at the 2′ position of thefive-membered sugar ring). Modified nucleotides include, but are notlimited to: 2′-modified nucleotides, 2′-O-methyl nucleotides(represented herein as a lower case letter ‘n’ in a nucleotidesequence), 2′-deoxy-2′-fluoro nucleotides (represented herein as Nf,also represented herein as 2′-fluoro nucleotide), 2′-deoxy nucleotides(represented herein as dN), 2′-methoxyethyl (2′-O-2-methoxylethyl)nucleotides (represented herein as NM or 2′-MOE), 2′-amino nucleotides,2′-alkyl nucleotides, 3′ to 3′ linkages (inverted) nucleotides(represented herein as invdN, invN, invn, invX), non-natural basecomprising nucleotides, bridged nucleotides, peptide nucleic acids,2′,3′-seco nucleotide mimics (unlocked nucleobase analogues, representedherein as N_(UNA) or NUNA), locked nucleotides (represented herein asN_(LNA) or NLNA), 3′-O-Methoxy (2′ intemucleotide linked) nucleotide(represented herein as 3′-OMen), 2′-F-Arabino nucleotides (representedherein as NfANA or Nf_(ANA)), morpholino nucleotides, vinyl phosphonatedeoxyribonucleotide (represented herein as vpdN), vinyl phosphonatenucleotides, and abasic nucleotides (represented herein as X or Ab). Itis not necessary for all positions in a given compound to be uniformlymodified. Conversely, more than one modification may be incorporated ina single F12 RNAi trigger or even in a single nucleotide thereof. TheF12 RNAi trigger sense strands and antisense strands may be synthesizedand/or modified by methods known in the art. Modification at onenucleotide is independent of modification of another nucleotide.

Modified nucleobases include synthetic and natural nucleobases, such as5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6substituted purines, including 2-aminopropyladenine, 5-propynyluraciland 5-propynylcytosine, 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and otheralkyl derivatives of adenine and guanine, 2-propyl and other alkylderivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil andcytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil),4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl andother 8-substituted adenines and guanines, 5-halo particularly 5-bromo,5-trifluoromethyl and other 5-substituted uracils and cytosines,7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine,7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.In some embodiments 20% or fewer of the modified nucleotides are2′-fluoro modified nucleotides.

In some embodiments, an F12 RNAi trigger sense strand contains a 2′-Fnucleotide at position 11 from the 3′ end. In some embodiments, an F12RNAi trigger sense strand contains a 2′-F nucleotide at position 12 fromthe 3′ end. In some embodiments, an F12 RNAi trigger sense strandcontains a 2′-F nucleotide at position 13 from the 3′ end. In someembodiments, an F12 RNAi trigger sense strand contains at least two 2′-Fnucleotides at positions 11, 12, and 13 from the 3′ end. In someembodiments, an F12 RNAi trigger sense strand contains 2′-F nucleotidesat positions 11 and 12, positions 11 and 13, or positions 12 and 13 fromthe 3′ end.

In some embodiments, an F12 RNAi trigger sense strand contains 2′-Fnucleotides at positions 11, 12, and 13 from the 3′ end.

In some embodiments, an F12 RNAi trigger antisense strand contains a2′-F nucleotide at position 2 from the 5′ end. In some embodiments, anF12 RNAi trigger antisense strand contains a 2′-F nucleotide at position14 from the 5′ end. In some embodiments, an F12 RNAi trigger antisensestrand contains 2′-F nucleotides at positions 2 and 14 from the 5′ end.In some embodiments, an F12 RNAi trigger contains at least two 2′-Fnucleotides at positions 11, 12, and 13 from the 3′ end of the sensestrand and at positions 2 and 14 from the 5′ end of the antisensestrand.

In some embodiments, an F12 RNAi trigger antisense strand contains a2′-F nucleotide at position 4 from the 5′ end. In some embodiments, anF12 RNAi trigger antisense strand contains a 2′-F nucleotide at position6 from the 5′ end. In some embodiments, an F12 RNAi trigger antisensestrand contains a 2′-F nucleotide at position 8 from the 5′ end. In someembodiments, an F12 RNAi trigger antisense strand contains a 2′-Fnucleotide at position 10 from the 5′ end. In some embodiments, an F12RNAi trigger antisense strand contains a 2′-F nucleotide at position 12from the 5′ end. In some embodiments, an F12 RNAi trigger antisensestrand contains at least two 2′-F nucleotides at positions 4, 6, 8, 10,and 12 from the 5′ end. In some embodiments, an F12 RNAi triggerantisense strand contains 2′-F nucleotides at positions 4 and 6,positions 4 and 8, positions 4 and 10, positions 4 and 12, positions 6and 8, positions 6 and 10, positions 6 and 12, positions 8 and 10,positions 8 and 12, or positions 10 and 12 from the 5′ end. In someembodiments, an F12 RNAi trigger antisense strand contains at three 2′-Fnucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end. In someembodiments, an F12 RNAi trigger antisense strand contains at least four2′-F nucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end. Insome embodiments, an F12 RNAi trigger antisense strand contains 2′-Fnucleotides at positions 4, 6, 8, and 10, positions 4, 6, 8, and 12,positions 4, 6, 10, and 12, positions 4, 8, 10, and 12 or positions 6,8, 10, and 12 from the 5′ end.

In some embodiments, an F12 RNAi trigger antisense strand contains a2′-F nucleotide at position 2 and/or position 14 and one, two, or three2′-F nucleotides at positions 11, 12, and 13 from the 5′ end. In someembodiments, an F12 RNAi trigger contains a 2′-F nucleotide at position2 and/or position 14 and one, two, or three 2′-F nucleotides atpositions 11, 12, and 13 from the 5′ end of the antisense strand, and atleast two 2′-F nucleotides at positions 11, 12, and 13 from the 3′ endof the sense strand.

In some embodiments, one or more nucleotides of an F12 RNAi trigger arelinked by non-phosphate-containing covalent intemucleoside linkages.Modified intemucleoside linkages or backbones include, for example,phosphorothioates, 5′-phosphorothioate group (represented herein as alower case ‘s’ before a nucleotide, as in sN, sn, sNf, or sdN), chiralphosphorothioates, thiophosphate, phosphorodithioates, phosphotriesters,aminoalkyl-phosphotriesters, methyl and other alkyl phosphonatesincluding 3′-alkylene phosphonates and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkyl-phosphonates, thionoalkylphosphotriesters, andboranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs ofthese, and those having inverted polarity wherein the adjacent pairs ofnucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Varioussalts, mixed salts and free-acid forms are also included. In someembodiments, a 2′ modification may be combined with modifiedintemucleoside linkages.

Modified intemucleoside linkages or backbones can lack a phosphorus atomtherein (e.g., oligonucleosides), which can be formed by short chainalkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl orcycloalkyl inter-sugar linkages, or one or more short chain heteroatomicor heterocyclic inter-sugar linkages. Such modified linkages orbackbones include those having morpholino linkages (formed in part fromthe sugar portion of a nucleoside); siloxane backbones; sulfide,sulfoxide and sulfone backbones; formacetyl and thioformacetylbackbones; methylene formacetyl and thioformacetyl backbones; alkenecontaining backbones; sulfamate backbones; methyleneimino andmethylenehydrazino backbones; sulfonate and sulfonamide backbones; amidebackbones; and others having mixed N, O, S, and CH₂ component parts.

In some embodiments, an F12 RNAi trigger can contain a modifiedbackbone, i.e. the F12 RNAi trigger contains a non-standard linkagebetween two nucleotides. In some embodiments, the modified backbone oneor more phosphorothioate linkages. For example, in some embodiments, asense strand of an F12 RNAi trigger can contain 1, 2, 3, or 4phosphorothioate linkages, an antisense strand of a F12 RNAi trigger cancontain 1, 2, 3, or 4 phosphorothioate linkages, or both the sensestrand and the antisense strand independently can contain 1, 2, 3, or 4phosphorothioate linkages.

In some embodiments, an F12 RNAi trigger sense strand contains twophosphorothioate intemucleotide linkages. In some embodiments, the twophosphorothioate intemucleotide linkages are between the nucleotides atpositions 1-3 from the 3′ end of the sense strand. In some embodiments,the two phosphorothioate intemucleotide linkages are between thenucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5′ endof the sense strand. In some embodiments, an F12 RNAi trigger antisensestrand contains four phosphorothioate intemucleotide linkages. In someembodiments, the four phosphorothioate intemucleotide linkages arebetween the nucleotides at positions 1-3 from the 5′ end of the sensestrand and between the nucleotides at positions 19-21, 20-22, 21-23,22-24, 23-25, or 24-26 from the 5′ end. In some embodiments, an F12 RNAitrigger contains two phosphorothioate intemucleotide linkages in thesense strand and four phosphorothioate intemucleotide linkages in theantisense strand.

Examples of antisense strands containing modified nucleotides areprovided in Table 2. Examples of sense strands containing modifiednucleotides are provided in Table 3. In Tables 2 and 3, the followingnotations are used to indicate modified nucleotides, targeting groupsand linking groups:

-   -   N=2′-OH (unmodified) ribonucleotide (capital letter without for        d indication)    -   n=2′-OMe modified nucleotide    -   Nf=2′-fluoro modified nucleotide    -   dN=2′-deoxy nucleotides    -   N_(UNA)=2′,3′-seco nucleotide mimics (unlocked nucleobase        analogs)    -   N_(LNA)=locked nucleotide    -   Nf_(ANA)=2′-F-Arabino nucleotide    -   NM=2′-methoxyethyl nucleotide    -   X=abasic ribose    -   R=ribitol    -   (invdN)=inverted deoxyribonucleotide (3′-3′ linked nucleotide)    -   (invX)=inverted abasic nucleotide    -   (invn)=inverted 2′-OMe nucleotide    -   s=phosphorothioate linked nucleotide    -   p=phosphate    -   vpdN=vinyl phosphonate deoxyribonucleotide    -   (3′OMen)=3′-OMe nucleotide

The following targeting groups and linking groups are listed in Tables 2and 3 and their chemical structures are provided further below in Table4: (NAG3), (C6-NAG3), (C6-PEG4-NAG3), (C6-C6-NAG3), (C6-C12-NAG3),(C11-NAG3), (C11-palm-NAG3), (C11-PEG3-NAG3), (NAG4), (NAG13), (NAG14),(NAG15), (NAG16), (NAG17), (NAG18), (NAG19), (NAG20), (NAG21), (NAG23),(Chol-TEG), (TEG-Chol), (Alk-C6), (Alk-BC9-C6), (Alk-C6-C6),(C6-C6-Alk), (Alk-C6-Ser), (Ser-C6-Alk), (Alk-NHCO-C6),(Alk-NHCO-SS-C6), (Alk-PEG4-C6), (Alk-PEG5-C6), (C6-PEG5-Alk),(Alk-PEG13-C6), (Alk-PEG5-Ser), (Alk-PEG13-Ser), (Alk-SS-C6),(C6-SS-Alk-Me), (Me-Alk-SS-C6), (C6-SMPT-Alk), (BCN), (DBCO-TEG),(C6-NH2), (NH2-C6), (NH2-C7), (NH2-Ser), (C3), (C12), (C6-SS-C6),(Cy5-C6), (Norbornene-C6), (Norbomene-Ser), (PAZ), (Ser-NH2), (Sp9),(Sp18), (Spermine), (Stearyl), (TetZ-C6) (NAG=N-Acetyl-galactosamine).

TABLE 2 Modified F12 RNAi trigger antisense strand sequences. SEQ IDAntisense Sequence Strand ID No. (5′ → 3′) AM00978-AS 451dTGfgUfgGfuAfgCfaCfaCfcAfgGfgdTsdT AM00979-AS 452dTGfgGfuGfgUfaGfcAfcAfcCfaGfgdTsdT AM00980-AS 453dTGfgGfgUfgGfuAfgCfaCfaCfcAfgdTsdT AM00981-AS 454dTCfaCfuUfuCfuUfgGfgCfuCfcAfadTsdT AM00982-AS 455dTUfcAfcUfuUfcUfuGfgGfcUfcCfadTsdT AM00983-AS 456dTUfuCfaCfuUfuCfuUfgGfgCfuCfcdTsdT AM00984-AS 457dTUfuUfcAfcUfuUfcUfuGfgGfcUfcdTsdT AM00985-AS 458dTCfuUfuCfaCfuUfuCfuUfgGfgCfudTsdT AM00986-AS 459dTUfcUfuUfcAfcUfuUfcUfuGfgGfcdTsdT AM00987-AS 460dTGfuCfuUfuCfaCfuUfuCfuUfgGfgdTsdT AM00988-AS 461dTGfgUfcUfuUfcAfcUfuUfcUfuGfgdTsdT AM00989-AS 462dTUfgGfuCfuUfuCfaCfuUfuCfuUfgdTsdT AM00990-AS 463dTAfgCfuGfaGfgCfuCfaAfaGfcAfcdTsdT AM00991-AS 464dTAfaGfcUfgAfgGfcUfcAfaAfgCfadTsdT AM00992-AS 465dTGfaAfgCfuGfaGfgCfuCfaAfaGfcdTsdT AM00993-AS 466dTGfaGfaAfgCfuGfaGfgCfuCfaAfadTsdT AM00994-AS 467dTGfcAfgGfcCfuGfgCfuGfgCfcAfgdTsdT AM00995-AS 468dTGfcCfcCfcUfcGfaAfcUfgGfuGfgdTsdT AM00996-AS 469dTUfuGfcGfgUfcAfcCfaCfaGfcCfcdTsdT AM00997-AS 470dTGfuUfgCfgGfuCfaCfcAfcAfgCfcdTsdT AM00998-AS 471dTUfgUfuGfcGfgUfcAfcCfaCfaGfcdTsdT AM00999-AS 472dTUfuGfuUfgCfgGfuCfaCfcAfcAfgdTsdT AM01000-AS 473dTCfuUfgUfuGfcGfgUfcAfcCfaCfadTsdT AM01001-AS 474dTGfcUfuGfuUfgCfgGfuCfaCfcAfcdTsdT AM01002-AS 475dTGfgCfuUfgUfuGfcGfgUfcAfcCfadTsdT AM01003-AS 476dTAfaGfcAfcUfuUfaUfuGfaGfuUfcdTsdT AM01004-AS 477dTAfaAfgCfaCfuUfuAfuUfgAfgUfudTsdT AM01005-AS 478dTCfaAfaGfcAfcUfuUfaUfuGfaGfudTsdT AM01006-AS 479dTUfcAfaAfgCfaCfuUfuAfuUfgAfgdTsdT AM01007-AS 480dTUfuCfaAfaGfcAfcUfuUfaUfuGfadTsdT AM01008-AS 481dTUfuUfcAfaAfgCfaCfuUfuAfuUfgdTsdT AM01009-AS 482dTUfuUfuCfaAfaGfcAfcUfuUfaUfudTsdT AM01377-AS 483dTCfaUfcCfgUfcCfgUfuGfgUfcCfadTsdT AM01378-AS 484dTGfcAfuCfcGfuCfcGfuUfgGfuCfcdTsdT AM01379-AS 485dTGfgCfaUfcCfgUfcCfgUfuGfgUfcdTsdT AM01380-AS 486dTUfgGfcAfuCfcGfuCfcGfuUfgGfudTsdT AM01381-AS 487dTAfuGfgCfaUfcCfgUfcCfgUfuGfgdTsdT AM01382-AS 488dTCfaUfgGfcAfuCfcGfuCfcGfuUfgdTsdT AM01383-AS 489dTUfcAfuGfgCfaUfcCfgUfcCfgUfudTsdT AM01384-AS 490dTCfuCfaUfgGfcAfuCfcGfuCfcGfudTsdT AM01385-AS 491dTCfaGfaGfcCfcUfcAfuGfgCfaUfcdTsdT AM01386-AS 492dTGfcAfgAfgCfcCfuCfaUfgGfcAfudTsdT AM01387-AS 493dTAfcCfcCfaGfgAfgCfaGfcAfgAfgdTsdT AM01388-AS 494dTGfgGfaAfgUfgGfcAfgGfgCfuCfcdTsdT AM01389-AS 495dTUfgGfuAfcAfgCfuGfcCfgGfuGfgdTsdT AM01390-AS 496dTCfuGfgUfcCfuGfaUfcAfaAfgUfudTsdT AM01391-AS 497dTGfcUfgGfuCfcUfgAfuCfaAfaGfudTsdT AM01392-AS 498dTUfcGfcUfgGfuCfcUfgAfuCfaAfadTsdT AM01393-AS 499dTCfcAfuCfgCfuGfgUfcCfuGfaUfcdTsdT AM01394-AS 500dTCfcCfaUfcGfcUfgGfuCfcUfgAfudTsdT AM01395-AS 501dTUfcCfcCfaUfcGfcUfgGfuCfcUfgdTsdT AM01396-AS 502dTCfuUfuCfuUfgGfgCfuCfcAfaAfcdTsdT AM01397-AS 503dTAfcUfuUfcUfuGfgGfcUfcCfaAfadTsdT AM01399-AS 504dTCfuGfaGfcCfcGfcGfgCfcAfuCfadTsdT AM01400-AS 505dTUfcCfgAfgGfcCfcAfcGfgCfuGfadTsdT AM01401-AS 506dTCfuCfcGfaGfgCfcCfaCfgGfcUfgdTsdT AM01402-AS 507dTCfcUfcCfgAfgGfcCfcAfcGfgCfudTsdT AM01403-AS 508dTGfgUfgGfcCfuCfcGfaGfgCfcCfadTsdT AM01404-AS 509dTAfgGfuGfgCfcUfcCfgAfgGfcCfcdTsdT AM01405-AS 510dTUfaGfgUfgGfcCfuCfcGfaGfgCfcdTsdT AM01406-AS 511dTGfuAfgGfuGfgCfcUfcCfgAfgGfcdTsdT AM01407-AS 512dTGfuCfcCfcAfgUfuCfcGfcGfcUfudTsdT AM01408-AS 513dTUfuCfcGfgCfaGfaAfgGfcGfuGfgdTsdT AM01409-AS 514dTGfuUfcCfgGfcAfgAfaGfgCfgUfgdTsdT AM01410-AS 515dTGfgUfuCfcGfgCfaGfaAfgGfcGfudTsdT AM01411-AS 516dTCfcGfgGfuUfcCfgGfcAfgAfaGfgdTsdT AM01412-AS 517dTUfcCfgGfgUfuCfcGfgCfaGfaAfgdTsdT AM01413-AS 518dTGfuCfcGfgGfuUfcCfgGfcAfgAfadTsdT AM01414-AS 519dTUfgUfcCfgGfgUfuCfcGfgCfaGfadTsdT AM01415-AS 520dTCfgUfuGfuCfcGfgGfuUfcCfgGfcdTsdT AM01416-AS 521dTUfcGfuUfgUfcCfgGfgUfuCfcGfgdTsdT AM01417-AS 522dTUfuCfcUfgGfuCfaGfgGfaAfgGfcdTsdT AM01418-AS 523dTGfuUfcCfuGfgUfcAfgGfgAfaGfgdTsdT AM01419-AS 524dTCfgUfuCfcUfgGfuCfaGfgGfaAfgdTsdT AM01420-AS 525dTCfcGfuUfcCfuGfgUfcAfgGfgAfadTsdT AM01421-AS 526dTGfcCfgUfuCfcUfgGfuCfaGfgGfadTsdT AM01422-AS 527dTCfaGfuGfgGfcCfgUfuCfcUfgGfudTsdT AM01423-AS 528dTAfgCfuCfaGfuGfgGfcCfgUfuCfcdTsdT AM01424-AS 529dTGfaAfgAfcAfgAfcUfcUfuGfcGfgdTsdT AM01425-AS 530dTUfgCfcGfgCfgCfaGfaAfaCfuGfudTsdT AM01426-AS 531dTGfgCfgAfuGfaGfgCfuGfcCfgGfcdTsdT AM01427-AS 532dTGfgGfcGfaUfgAfgGfcUfgCfcGfgdTsdT AM01428-AS 533dTGfgGfgCfgAfuGfaGfgCfuGfcCfgdTsdT AM01429-AS 534dTAfcCfcAfgCfaGfgGfgGfcGfaUfgdTsdT AM01430-AS 535dTGfcAfcCfcAfgCfaGfgGfgGfcGfadTsdT AM01431-AS 536dTAfgCfaCfcCfaGfcAfgGfgGfgCfgdTsdT AM01432-AS 537dTUfcAfgCfaCfcCfaGfcAfgGfgGfgdTsdT AM01433-AS 538dTCfcGfaGfcAfcCfaCfcGfuCfaGfadTsdT AM01434-AS 539dTGfgCfcGfaGfcAfcCfaCfcGfuCfadTsdT AM01435-AS 540dTUfgGfcCfgAfgCfaCfcAfcCfgUfcdTsdT AM01436-AS 541dTUfcCfuGfgCfcGfaGfcAfcCfaCfcdTsdT AM01437-AS 542dTCfaGfcUfgCfcGfuCfcGfcAfuCfcdTsdT AM01438-AS 543dTGfgAfgCfgCfgCfaGfcUfgCfcGfudTsdT AM01439-AS 544dTAfcGfuAfaGfgCfgAfcAfgGfaGfcdTsdT AM01440-AS 545dTCfuGfaAfcGfuAfaGfgCfgAfcAfgdTsdT AM01441-AS 546dTCfuGfgCfaUfaUfuCfcUfcCfgCfcdTsdT AM01442-AS 547dTAfgCfuGfgCfaUfaUfuCfcUfcCfgdTsdT AM01443-AS 548dTGfaAfgCfuGfgCfaUfaUfuCfcUfcdTsdT AM01444-AS 549dTGfgAfaGfcUfgGfcAfuAfuUfcCfudTsdT AM01445-AS 550dTCfgGfgCfcUfcCfgGfaAfuCfaCfcdTsdT AM01446-AS 551dTGfcCfaCfuCfuCfuCfaCfuGfcGfgdTsdT AM01447-AS 552dTAfgCfcAfcUfcUfcUfcAfcUfgCfgdTsdT AM01514-AS 553dTAfaCfaGfaGfcCfgUfcAfuGfgCfgdTsdT AM01515-AS 554dTCfaAfcAfgAfgCfcGfuCfaUfgGfcdTsdT AM01516-AS 555dTAfcAfaCfaGfaGfcCfgUfcAfuGfgdTsdT AM01517-AS 556dTAfaCfaAfcAfgAfgCfcGfuCfaUfgdTsdT AM01518-AS 557dTGfaAfcAfaCfaGfaGfcCfgUfcAfudTsdT AM01519-AS 558dTGfgAfaCfaAfcAfgAfgCfcGfuCfadTsdT AM01520-AS 559dTCfgGfuGfgUfaCfuGfaAfaGfgGfadTsdT AM01521-AS 560dTUfuGfuGfgAfuGfcAfuUfuGfuGfgdTsdT AM01522-AS 561dTCfaAfgCfaGfuAfuCfcCfcAfuUfgdTsdT AM01523-AS 562dTCfuCfcAfaGfcAfgUfaUfcCfcCfadTsdT AM01524-AS 563dTGfcUfcCfaAfgCfaGfuAfuCfcCfcdTsdT AM01525-AS 564dTGfgGfcUfcCfaAfgCfaGfuAfuCfcdTsdT AM01526-AS 565dTGfuGfuUfuGfcUfgCfaAfuGfgUfcdTsdT AM01527-AS 566dTUfuCfcGfgUfaGfgUfgGfcCfuCfcdTsdT AM01528-AS 567dTGfuUfcCfgGfuAfgGfuGfgCfcUfcdTsdT AM01529-AS 568dTUfgUfuCfcGfgUfaGfgUfgGfcCfudTsdT AM01530-AS 569dTCfuCfaGfuCfaUfgUfuCfcGfgUfadTsdT AM01531-AS 570dTGfaCfgUfgUfgUfcAfuUfaUfcUfgdTsdT AM01532-AS 571dTGfgAfcGfuGfuGfuCfaUfuAfuCfudTsdT AM01533-AS 572dTUfgGfaCfgUfgUfgUfcAfuUfaUfcdTsdT AM01534-AS 573dTAfuGfgAfcGfuGfuGfuCfaUfuAfudTsdT AM01535-AS 574dTAfcCfaUfgGfaCfgUfgUfgUfcAfudTsdT AM01536-AS 575dTAfgUfcCfgCfcCfaCfcAfcGfcGfcdTsdT AM01537-AS 576dTUfaGfuCfcGfcCfcAfcCfaCfgCfgdTsdT AM01538-AS 577dTCfuAfgUfcCfgCfcCfaCfcAfcGfcdTsdT AM01539-AS 578dTAfcUfaGfuCfcGfcCfcAfcCfaCfgdTsdT AM01540-AS 579dTCfaGfaGfcCfaCfuAfgUfcCfgCfcdTsdT AM01541-AS 580dTGfuUfcCfuCfgGfgCfgCfuGfgCfcdTsdT AM01542-AS 581dTAfgUfaCfcAfcUfgUfcAfgUfuCfcdTsdT AM01543-AS 582dTUfcUfuGfaCfcAfaGfuAfcCfaCfudTsdT AM01544-AS 583dTGfaUfcUfuGfaCfcAfaGfuAfcCfadTsdT AM01545-AS 584dTCfgAfuCfuUfgAfcCfaAfgUfaCfcdTsdT AM01546-AS 585dTCfgAfuCfuUfgAfcCfaAfgUfaCfcdTsdT AM01547-AS 586dTUfcGfuGfaAfgGfcGfgUfaGfgAfgdTsdT AM01548-AS 587dTCfcUfcGfuGfaAfgGfcGfgUfaGfgdTsdT AM01549-AS 588dTCfcCfuCfgUfgAfaGfgCfgGfuAfgdTsdT AM01550-AS 589dTCfgCfaGfaGfcAfcUfgUfcUfcAfgdTsdT AM01551-AS 590dTCfuUfcAfgCfcCfcCfuCfgAfaCfudTsdT AM01552-AS 591dTUfcUfuCfaGfcCfcCfcUfcGfaAfcdTsdT AM01553-AS 592dTAfuUfcUfuCfaGfcCfcCfcUfcGfadTsdT AM01554-AS 593dTUfcUfcCfgUfgCfaCfgUfuAfgAfgdTsdT AM01555-AS 594dTCfgUfcUfcCfgUfgCfaCfgUfuAfgdTsdT AM01556-AS 595dTUfgGfcGfuCfuCfcGfuGfcAfcGfudTsdT AM01621-AS 596dACfuUfuCfaCfuUfuCfuUfgGfgCfudTsdT AM01622-AS 597dTCfuUfuC_(UNA)aCfuUfuCfuUfgGfgCfudTsdT AM01623-AS 598dTCfuUfuCfA_(UNA)CfuUfuCfuUfgGfgCfudTsdT AM01624-AS 599dTUfcUfuU_(UNA)cAfcUfuUfcUfuGfgGfcdTsdT AM01625-AS 600dTUfcUfuUfC_(UNA)AfcUfuUfcUfuGfgGfcdTsdT AM01626-AS 601dTGfuCfuU_(UNA)uCfaCfuUfuCfuUfgGfgdTsdT AM01627-AS 602dTGfuCfuUfU_(UNA)CfaCfuUfuCfuUfgGfgdTsdT AM01628-AS 603dAGfgUfcUfuUfcAfcUfuUfcUfuGfgdTsdT AM01629-AS 604dTGfgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgdTsdT AM01630-AS 605dTGfgUfcUfU_(UNA)UfcAfcUfuUfcUfuGfgdTsdT AM01631-AS 606dTUfgGfuC_(UNA)uUfuCfaCfuUfuCfuUfgdTsdT AM01632-AS 607dTUfgGfuCfU_(UNA)UfuCfaCfuUfuCfuUfgdTsdT AM01633-AS 608dTGfaGfaA_(UNA)gCfuGfaGfgCfuCfaAfadTsdT AM01634-AS 609dTGfaGfaAfG_(UNA)CfuGfaGfgCfuCfaAfadTsdT AM01903-AS 610vpdTGfuCfuU_(UNA)uCfaCfuUfuCfuUfgGfgdTsdT AM01904-AS 611vpdTGfuCfuU_(UNA)uCfaCfuUfuCfuUfgGfgsdTsdT AM01906-AS 612vpdTGfgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgdTsdT AM01907-AS 613vpdTGfgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgsdTsdT AM01909-AS 614vpdTGfaGfaA_(UNA)gCfuGfaGfgCfuCfaAfadTsdT AM01910-AS 615vpdTGfaGfaA_(UNA)gCfuGfaGfgCfuCfaAfasdTsdT AM01915-AS 616vpdTGfgUfcUfU_(UNA)UfcAfcUfuUfcUfuGfgdTsdT AM01916-AS 617vpdTGfgUfcUfU_(UNA)UfcAfcUfuUfcUfuGfgsdTsdT AM01917-AS 618dTsGfsgUfcUfU_(UNA)UfcAfcUfuUfcUfuGfgsdTsdT AM01918-AS 619dTsGfsuCfuU_(UNA)uCfaCfuUfuCfuUfgGfgsdTsdT AM01919-AS 620dTsGfsgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgsdTsdT AM01920-AS 621dTsGfsaGfaA_(UNA)gCfuGfaGfgCfuCfaAfasdTsdT AM01921-AS 622dTsGfsuCfuU_(UNA)uCfaCfuuuCfuUfgGfgsdTsdT AM01923-AS 623dTsGfsgUfcU_(UNA)uUfcAfcuuUfcUfuGfgsdTsdT AM01925-AS 624dTsGfsaGfaA_(UNA)gCfuGfaggCfuCfaAfasdTsdT AM01927-AS 625dTsGfsgUfcUfU_(UNA)UfcAfcuuUfcUfuGfgsdTsdT AM01928-AS 626usGfsgUfcUfU_(UNA)UfcAfcuuUfcUfuGfgsdTsdT AM01929-AS 627usGfsgUfcU_(UNA)uUfcAfcuuUfcUfuGfgsdTsdT AM01930-AS 628usGfsgUfcUuNAuUfcAfcuuUfcUfuGfgGfcsusc AM01931-AS 629usGfsgUfcUfU_(UNA)UfcAfcuuUfcUfuGfgGfcsusc AM01996-AS 630dTGfgUfcU_(UNA)uUfcAfcuuUfcUfuGfgdTsdT AM01997-AS 631dTGfgUfcUfU_(UNA)UfcAfcuuUfcUfuGfgdTsdT AM02060-AS 632dTGfuCfuU_(UNA)uCfaCfuuuCfuUfgGfgdTsdT AM02062-AS 633dTGfaGfaA_(UNA)gCfuGfaggCfuCfaAfadTsdT AM02112-AS 634pdTGfgUfcUfuUfcAfcUfuUfcUfuGfgdTsdT AM02113-AS 635pdTGfgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgdTsdT AM02164-AS 636dTsGfsgUfcU_(UNA)uUfcAfcuuUfcUfuGfgGfcuscsuAu AM02165-AS 637dTsGfsgUfcUfuUfcAfcuuUfcUfuGfgGfcuscsuAu AM02166-AS 638dTsGfsgUfcU_(UNA)uUfcAfcuuUfcUfuGfgGfcucusdTsdT AM02167-AS 639dTsGfsgUfcUfuUfcAfcuuUfcUfuGfgGfcucusdTsdT AM02171-AS 640dTsGfsgUfcUfuUfcAfcuuUfcUfuGfgGfcuscsu AM02172-AS 641dTsGfsgUfcUfuUfcAfcuuUfcUfuGfgGfcsusc AM02197-AS 642dTsCfsuUfuCfaCfuUfucuUfgGfgCfuCfcsasa AM02198-AS 643dTsUfscUfuUfcAfcUfuucUfuGfgGfcUfcscsa AM02199-AS 644dTsGfsuCfuUfuCfaCfuuuCfuUfgGfgCfuscsc AM02200-AS 645dTsUfsgGfuCfuUfuCfacuUfuCfuUfgGfgscsu AM02201-AS 646dTsGfsaGfaAfgCfuGfaggCfuCfaAfaGfcsasc AM02208-AS 647dTsGfsgUfcUfuUfcAfcuuUfcUfuGfgGfcsuscuAu AM02331-AS 648dTsGfsgUfcU_(UNA)uUfcAfcUfuUfcUfuGfgGfcuscsuAu AM02332-AS 649dTsGfsgUfcUfU_(UNA)UfcAfcUfuUfcUfuGfgGfcuscsuAu AM02333-AS 650dTsGfsgUfcUfuU_(UNA)cAfcUfuUfcUfuGfgGfcuscsuAu AM02334-AS 651dTsGfsgUfcUfuUfC_(UNA)AfcUfuUfcUfuGfgGfcuscsuAu AM02335-AS 652dTsGfsgUfcUfuUfcA_(UNA)cUfuUfcUfuGfgGfcuscsuAu AM02336-AS 653dTsGfsgUfcUfuUfcAfC_(UNA)UfuUfcUfuGfgGfcuscsuAu AM02337-AS 654dTsGfsgUfcUfuUfcAfcU_(UNA)uUfcUfuGfgGfcuscsuAu AM02338-AS 655dTsGfsgUfcUfuUfcAfcUfU_(UNA)UfcUfuGfgGfcuscsuAu AM02339-AS 656dTsGfsgUfcUfuUfcAfcUfuU_(UNA)cUfuGfgGfcuscsuAu AM02340-AS 657dTsGfsgUfcUfuUfcAfcUfuUfC_(UNA)UfuGfgGfcuscsuAu AM02348-AS 658dTsGfsgUfcUfuUfcAfcUfuUfcUfuGfgGfcuscsuAu AM02349-AS 659dTsGfsgUfcUfuUfcAfcuUfUfcUfuGfgGfcuscsuAu AM02350-AS 660dTsGfsgUfcUfuUfcAfcuUfucUfuGfgGfcuscsuAu AM02354-AS 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2088dTAfaGfcAfcCfaCfgGfgCfgGfaUfgdTsdT 2089dTGfaAfgCfaCfcAfcGfgGfcGfgAfudTsdT 2090dTAfcGfaAfgCfaCfcAfcGfgGfcGfgdTsdT 2091dTGfcAfcGfaAfgCfaCfcAfcGfgGfcdTsdT 2092dTCfaUfgAfgUfgGfgAfcAfuGfaAfgdTsdT 2093dTUfuCfgGfcGfgUfgCfcGfgCfuGfcdTsdT 2094dTAfcAfgAfcUfcUfuGfcGfgAfgCfcdTsdT 2095dTGfaCfaGfaCfuCfuUfgCfgGfaGfcdTsdT 2096dTGfuCfaUfcGfaAfgAfcAfgAfcUfcdTsdT 2097dTGfgUfcAfuCfgAfaGfaCfaGfaCfudTsdT 2098dTAfcGfcGfgGfuCfaUfcGfaAfgAfcdTsdT 2099dTGfaCfgCfgGfgUfcAfuCfgAfaGfadTsdT 2100dTCfgAfcGfcGfgGfuCfaUfcGfaAfgdTsdT 2101dTAfcGfaCfgCfgGfgUfcAfuCfgAfadTsdT 2102dTAfaCfgAfcGfcGfgGfuCfaUfcGfadTsdT 2103dTCfaAfcGfaCfgCfgGfgUfcAfuCfgdTsdT 2104dTCfcAfaCfgAfcGfcGfgGfuCfaUfcdTsdT 2105dTCfgCfcAfaCfgAfcGfcGfgGfuCfadTsdT 2106dTCfcGfcCfaAfcGfaCfgCfgGfgUfcdTsdT 2107dTCfcGfcGfuAfgCfgCfcAfcCfaGfcdTsdT 2108dTCfcCfcGfcGfuAfgCfgCfcAfcCfadTsdT 2109dTGfcCfcCfgCfgUfaGfcGfcCfaCfcdTsdT 2110dTCfgCfcCfcGfcGfuAfgCfgCfcAfcdTsdT 2111dTGfgGfuGfcGfcCfcCfgCfgUfaGfcdTsdT 2112dTGfcGfaUfgUfaGfgGfgUfgCfgCfcdTsdT 2113dTCfgCfgGfcGfaUfgUfaGfgGfgUfgdTsdT 2114dTAfgCfgCfgGfcGfaUfgUfaGfgGfgdTsdT 2115dTCfaGfcGfcGfgCfgAfuGfuAfgGfgdTsdT 2116dTAfcAfgCfgCfgGfcGfaUfgUfaGfgdTsdT 2117dTUfaCfaGfcGfcGfgCfgAfuGfuAfgdTsdT 2118dTGfuAfcAfgCfgCfgGfcGfaUfgUfadTsdT 2119dTCfaGfuAfcAfgCfgCfgGfcGfaUfgdTsdT 2120dTCfcCfaGfuAfcAfgCfgCfgGfcGfadTsdT 2121dTAfuGfaGfgCfuGfcCfgGfcGfcAfgdTsdT 2122dTCfgUfcAfgAfuCfcUfcGfgGfuGfcdTsdT 2123dTCfcGfuCfaGfaUfcCfuCfgGfgUfgdTsdT 2124dTCfgAfgAfaGfgCfcUfcGfuGfcAfadTsdT 2125dTGfcGfaGfaAfgGfcCfuCfgUfgCfadTsdT 2126dTAfaCfaGfaGfcCfaGfgUfcGfuGfcdTsdT 2127dTCfuGfaAfgGfcGfcAfaCfaGfaGfcdTsdT 2128dTAfuCfcUfcCfuGfaAfgGfcGfcAfadTsdT 2129dTAfgCfgCfgCfaGfcUfgCfcGfuCfcdTsdT 2130dTUfaAfgGfcGfaCfaGfgAfgCfgCfgdTsdT 2131dTGfuAfaGfgCfgAfcAfgGfaGfcGfcdTsdT 2132dTCfgUfaAfgGfcGfaCfaGfgAfgCfgdTsdT 2133dTAfcGfuAfaGfgCfgAfcAfgGfaGfcdTsdT 2134dTAfaCfgUfaAfgGfcGfaCfaGfgAfgdTsdT 2135dTGfaAfcGfuAfaGfgCfgAfcAfgGfadTsdT 2136dTGfcUfgAfaCfgUfaAfgGfcGfaCfadTsdT 2137dTGfgCfuGfaAfcGfuAfaGfgCfgAfcdTsdT 2138dTCfgGfcUfgAfaCfgUfaAfgGfcGfadTsdT 2139dTCfcGfgCfuGfaAfcGfuAfaGfgCfgdTsdT 2140dTAfcCfgGfcUfgAfaCfgUfaAfgGfcdTsdT 2141dTAfcAfcCfgGfcUfgAfaCfgUfaAfgdTsdT 2142dTGfgCfaCfaCfcGfgCfuGfaAfcGfudTsdT 2143dTCfcGfcUfuGfgCfaGfgCfaCfaCfcdTsdT 2144dTCfcCfcCfuCfgAfaCfuGfgUfgGfcdTsdT 2145dTCfgCfcCfcCfuCfgAfaCfuGfgUfgdTsdT 2146dTAfuUfcCfuCfcGfcCfcCfcUfcGfadTsdT 2147dTUfcGfaGfgAfaCfcCfuGfcGfcAfgdTsdT 2148dTCfuCfgAfgGfaAfcCfcUfgCfgCfadTsdT 2149dTCfcUfcGfaGfgAfaCfcCfuGfcGfcdTsdT 2150dTGfgUfgCfcGfcCfcUfcGfaGfgAfadTsdT 2151dTAfuCfgGfuGfcCfgCfcCfuCfgAfgdTsdT 2152dTCfaUfcGfgUfgCfcGfcCfcUfcGfadTsdT 2153dTGfgGfuGfaGfcCfgGfcGfcUfcUfgdTsdT 2154dTGfcCfcGfaUfcCfcCfaGfcUfgAfudTsdT 2155dTGfgUfcAfcCfaCfaGfcCfcGfaUfcdTsdT 2156dTAfcGfcCfuGfgCfuUfgUfuGfcGfgdTsdT 2157dTAfgAfcGfcCfuGfgCfuUfgUfuGfcdTsdT 2158dTAfcAfuCfgGfuGfuAfgAfcGfcCfudTsdT 2159dTCfaCfaUfcGfgUfgUfaGfaCfgCfcdTsdT 2160dTCfcAfcAfuCfgGfuGfuAfgAfcGfcdTsdT 2161dTGfuGfuGfcUfcCfcGfgAfuCfcAfgdTsdT 2162dTGfaGfuCfcCfuGfaGfcAfaUfcAfgdTsdT 2163dTGfaUfgAfgUfcCfcUfgAfgCfaAfudTsdT 2164dTGfcAfcUfuUfaUfuGfaGfuUfcCfudTsdT 2165dTAfgCfaCfuUfuAfuUfgAfgUfuCfcdTsdT

TABLE 3 Modified F12 RNAi trigger sense strand sequences. SEQ ID SenseSequence Strand ID No. (5′ → 3′) AM00913-SS 837CfcCfuGfgUfgUfgCfuAfcCfaCfcAf(invdT) AM00914-SS 838CfcUfgGfuGfuGfcUfaCfcAfcCfcAf(invdT) AM00915-SS 839CfuGfgUfgUfgCfuAfcCfaCfcCfcAf(invdT) AM00916-SS 840UfuGfgAfgCfcCfaAfgAfaAfgUfgAf(invdT) AM00917-SS 841UfgGfaGfcCfcAfaGfaAfaGfuGfaAf(invdT) AM00918-SS 842GfgAfgCfcCfaAfgAfaAfgUfgAfaAf(invdT) AM00919-SS 843GfaGfcCfcAfaGfaAfaGfuGfaAfaAf(invdT) AM00920-SS 844AfgCfcCfaAfgAfaAfgUfgAfaAfgAf(invdT) AM00921-SS 845GfcCfcAfaGfaAfaGfuGfaAfaGfaAf(invdT) AM00922-SS 846CfcCfaAfgAfaAfgUfgAfaAfgAfcAf(invdT) AM00923-SS 847CfcAfaGfaAfaGfuGfaAfaGfaCfcAf(invdT) AM00924-SS 848CfaAfgAfaAfgUfgAfaAfgAfcCfaAf(invdT) AM00925-SS 849GfuGfcUfuUfgAfgCfcUfcAfgCfuAf(invdT) AM00926-SS 850UfgCfuUfuGfaGfcCfuCfaGfcUfuAf(invdT) AM00927-SS 851GfcUfuUfgAfgCfcUfcAfgCfuUfcAf(invdT) AM00928-SS 852UfuUfgAfgCfcUfcAfgCfuUfcUfcAf(invdT) AM00929-SS 853CfuGfgCfcAfgCfcAfgGfcCfuGfcAf(invdT) AM00930-SS 854CfcAfcCfaGfuUfcGfaGfgGfgGfcAf(invdT) AM00931-SS 855GfgGfcUfgUfgGfuGfaCfcGfcAfaAf(invdT) AM00932-SS 856GfgCfuGfuGfgUfgAfcCfgCfaAfcAf(invdT) AM00933-SS 857GfcUfgUfgGfuGfaCfcGfcAfaCfaAf(invdT) AM00934-SS 858CfuGfuGfgUfgAfcCfgCfaAfcAfaAf(invdT) AM00935-SS 859UfgUfgGfuGfaCfcGfcAfaCfaAfgAf(invdT) AM00936-SS 860GfuGfgUfgAfcCfgCfaAfcAfaGfcAf(invdT) AM00937-SS 861UfgGfuGfaCfcGfcAfaCfaAfgCfcAf(invdT) AM00938-SS 862GfaAfcUfcAfaUfaAfaGfuGfcUfuAf(invdT) AM00939-SS 863AfaCfuCfaAfuAfaAfgUfgCfuUfuAf(invdT) AM00940-SS 864AfcUfcAfaUfaAfaGfuGfcUfuUfgAf(invdT) AM00941-SS 865CfuCfaAfuAfaAfgUfgCfuUfuGfaAf(invdT) AM00942-SS 866UfcAfaUfaAfaGfuGfcUfuUfgAfaAf(invdT) AM00943-SS 867CfaAfuAfaAfgUfgCfuUfuGfaAfaAf(invdT) AM00944-SS 868AfaUfaAfaGfuGfcUfuUfgAfaAfaAf(invdT) AM01307-SS 869UfgGfaCfcAfaCfgGfaCfgGfaUfgAf(invdT) AM01308-SS 870GfgAfcCfaAfcGfgAfcGfgAfuGfcAf(invdT) AM01309-SS 871GfaCfcAfaCfgGfaCfgGfaUfgCfcAf(invdT) AM01310-SS 872AfcCfaAfcGfgAfcGfgAfuGfcCfaAf(invdT) AM01311-SS 873CfcAfaCfgGfaCfgGfaUfgCfcAfuAf(invdT) AM01312-SS 874CfaAfcGfgAfcGfgAfuGfcCfaUfgAf(invdT) AM01313-SS 875AfaCfgGfaCfgGfaUfgCfcAfuGfaAf(invdT) AM01314-SS 876AfcGfgAfcGfgAfuGfcCfaUfgAfgAf(invdT) AM01315-SS 877GfaUfgCfcAfuGfaGfgGfcUfcUfgAf(invdT) AM01316-SS 878AfuGfcCfaUfgAfgGfgCfuCfuGfcAf(invdT) AM01317-SS 879CfuCfuGfcUfgCfuCfcUfgGfgGfuAf(invdT) AM01318-SS 880GfgAfgCfcCfuGfcCfaCfuUfcCfcAf(invdT) AM01319-SS 881CfcAfcCfgGfcAfgCfuGfuAfcCfaAf(invdT) AM01320-SS 882AfaCfuUfuGfaUfcAfgGfaCfcAfgAf(invdT) AM01321-SS 883AfcUfuUfgAfuCfaGfgAfcCfaGfcAf(invdT) AM01322-SS 884UfuUfgAfuCfaGfgAfcCfaGfcGfaAf(invdT) AM01323-SS 885GfaUfcAfgGfaCfcAfgCfgAfuGfgAf(invdT) AM01324-SS 886AfuCfaGfgAfcCfaGfcGfaUfgGfgAf(invdT) AM01325-SS 887CfaGfgAfcCfaGfcGfaUfgGfgGfaAf(invdT) AM01326-SS 888GfuUfuGfgAfgCfcCfaAfgAfaAfgAf(invdT) AM01327-SS 889UfuUfgGfaGfcCfcAfaGfaAfaGfuAf(invdT) AM01328-SS 890UfgAfuGfgCfcGfcGfgGfcUfcAfgAf(invdT) AM01329-SS 891UfcAfgCfcGfuGfgGfcCfuCfgGfaAf(invdT) AM01330-SS 892CfaGfcCfgUfgGfgCfcUfcGfgAfgAf(invdT) AM01331-SS 893AfgCfcGfuGfgGfcCfuCfgGfaGfgAf(invdT) AM01332-SS 894UfgGfgCfcUfcGfgAfgGfcCfaCfcAf(invdT) AM01333-SS 895GfgGfcCfuCfgGfaGfgCfcAfcCfuAf(invdT) AM01334-SS 896GfgCfcUfcGfgAfgGfcCfaCfcUfaAf(invdT) AM01335-SS 897GfcCfuCfgGfaGfgCfcAfcCfuAfcAf(invdT) AM01336-SS 898AfaGfcGfcGfgAfaCfuGfgGfgAfcAf(invdT) AM01337-SS 899CfcAfcGfcCfuUfcUfgCfcGfgAfaAf(invdT) AM01338-SS 900CfaCfgCfcUfuCfuGfcCfgGfaAfcAf(invdT) AM01339-SS 901AfcGfcCfuUfcUfgCfcGfgAfaCfcAf(invdT) AM01340-SS 902CfcUfuCfuGfcCfgGfaAfcCfcGfgAf(invdT) AM01341-SS 903CfuUfcUfgCfcGfgAfaCfcCfgGfaAf(invdT) AM01342-SS 904UfuCfuGfcCfgGfaAfcCfcGfgAfcAf(invdT) AM01343-SS 905UfcUfgCfcGfgAfaCfcCfgGfaCfaAf(invdT) AM01344-SS 906GfcCfgGfaAfcCfcGfgAfcAfaCfgAf(invdT) AM01345-SS 907CfcGfgAfaCfcCfgGfaCfaAfcGfaAf(invdT) AM01346-SS 908GfcCfuUfcCfcUfgAfcCfaGfgAfaAf(invdT) AM01347-SS 909CfcUfuCfcCfuGfaCfcAfgGfaAfcAf(invdT) AM01348-SS 910CfuUfcCfcUfgAfcCfaGfgAfaCfgAf(invdT) AM01349-SS 911UfuCfcCfuGfaCfcAfgGfaAfcGfgAf(invdT) AM01350-SS 912UfcCfcUfgAfcCfaGfgAfaCfgGfcAf(invdT) AM01351-SS 913AfcCfaGfgAfaCfgGfcCfcAfcUfgAf(invdT) AM01352-SS 914GfgAfaCfgGfcCfcAfcUfgAfgCfuAf(invdT) AM01353-SS 915CfcGfcAfaGfaGfuCfuGfuCfuUfcAf(invdT) AM01354-SS 916AfcAfgUfuUfcUfgCfgCfcGfgCfaAf(invdT) AM01355-SS 917GfcCfgGfcAfgCfcUfcAfuCfgCfcAf(invdT) AM01356-SS 918CfcGfgCfaGfcCfuCfaUfcGfcCfcAf(invdT) AM01357-SS 919CfgGfcAfgCfcUfcAfuCfgCfcCfcAf(invdT) AM01358-SS 920CfaUfcGfcCfcCfcUfgCfuGfgGfuAf(invdT) AM01359-SS 921UfcGfcCfcCfcUfgCfuGfgGfuGfcAf(invdT) AM01360-SS 922CfgCfcCfcCfuGfcUfgGfgUfgCfuAf(invdT) AM01361-SS 923CfcCfcCfuGfcUfgGfgUfgCfuGfaAf(invdT) AM01362-SS 924UfcUfgAfcGfgUfgGfuGfcUfcGfgAf(invdT) AM01363-SS 925UfgAfcGfgUfgGfuGfcUfcGfgCfcAf(invdT) AM01364-SS 926GfaCfgGfuGfgUfgCfuCfgGfcCfaAf(invdT) AM01365-SS 927GfgUfgGfuGfcUfcGfgCfcAfgGfaAf(invdT) AM01366-SS 928GfgAfuGfcGfgAfcGfgCfaGfcUfgAf(invdT) AM01367-SS 929AfcGfgCfaGfcUfgCfgCfgCfuCfcAf(invdT) AM01368-SS 930GfcUfcCfuGfuCfgCfcUfuAfcGfuAf(invdT) AM01369-SS 931CfuGfuCfgCfcUfuAfcGfuUfcAfgAf(invdT) AM01370-SS 932GfgCfgGfaGfgAfaUfaUfgCfcAfgAf(invdT) AM01371-SS 933CfgGfaGfgAfaUfaUfgCfcAfgCfuAf(invdT) AM01372-SS 934GfaGfgAfaUfaUfgCfcAfgCfuUfcAf(invdT) AM01373-SS 935AfgGfaAfuAfuGfcCfaGfcUfuCfcAf(invdT) AM01374-SS 936GfgUfgAfuUfcCfgGfaGfgCfcCfgAf(invdT) AM01375-SS 937CfcGfcAfgUfgAfgAfgAfgUfgGfcAf(invdT) AM01376-SS 938CfgCfaGfuGfaGfaGfaGfuGfgCfuAf(invdT) AM01471-SS 939CfgCfcAfuGfaCfgGfcUfcUfgUfuAf(invdT) AM01472-SS 940GfcCfaUfgAfcGfgCfuCfuGfuUfgAf(invdT) AM01473-SS 941CfcAfuGfaCfgGfcUfcUfgUfuGfuAf(invdT) AM01474-SS 942CfaUfgAfcGfgCfuCfuGfuUfgUfuAf(invdT) AM01475-SS 943AfuGfaCfgGfcUfcUfgUfuGfuUfcAf(invdT) AM01476-SS 944UfgAfcGfgCfuCfuGfuUfgUfuCfcAf(invdT) AM01477-SS 945UfcCfcUfuUfcAfgUfaCfcAfcCfgAf(invdT) AM01478-SS 946CfcAfcAfaAfuGfcAfuCfcAfcAfaAf(invdT) AM01479-SS 947CfaAfuGfgGfgAfuAfcUfgCfuUfgAf(invdT) AM01480-SS 948UfgGfgGfaUfaCfuGfcUfuGfgAfgAf(invdT) AM01481-SS 949GfgGfgAfuAfcUfgCfuUfgGfaGfcAf(invdT) AM01482-SS 950GfgAfuAfcUfgCfuUfgGfaGfcCfcAf(invdT) AM01483-SS 951GfaCfcAfuUfgCfaGfcAfaAfcAfcAf(invdT) AM01484-SS 952GfgAfgGfcCfaCfcUfaCfcGfgAfaAf(invdT) AM01485-SS 953GfaGfgCfcAfcCfuAfcCfgGfaAfcAf(invdT) AM01486-SS 954AfgGfcCfaCfcUfaCfcGfgAfaCfaAf(invdT) AM01487-SS 955UfaCfcGfgAfaCfaUfgAfcUfgAfgAf(invdT) AM01488-SS 956CfaGfaUfaAfuGfaCfaCfaCfgUfcAf(invdT) AM01489-SS 957AfgAfuAfaUfgAfcAfcAfcGfuCfcAf(invdT) AM01490-SS 958GfaUfaAfuGfaCfaCfaCfgUfcCfaAf(invdT) AM01491-SS 959AfuAfaUfgAfcAfcAfcGfuCfcAfuAf(invdT) AM01492-SS 960AfuGfaCfaCfaCfgUfcCfaUfgGfuAf(invdT) AM01493-SS 961GfcGfcGfuGfgUfgGfgCfgGfaCfuAf(invdT) AM01494-SS 962CfgCfgUfgGfuGfgGfcGfgAfcUfaAf(invdT) AM01495-SS 963GfcGfuGfgUfgGfgCfgGfaCfuAfgAf(invdT) AM01496-SS 964CfgUfgGfuGfgGfcGfgAfcUfaGfuAf(invdT) AM01497-SS 965GfgCfgGfaCfuAfgUfgGfcUfcUfgAf(invdT) AM01498-SS 966GfgCfcAfgCfgCfcCfgAfgGfaAfcAf(invdT) AM01499-SS 967GfgAfaCfuGfaCfaGfuGfgUfaCfuAf(invdT) AM01500-SS 968AfgUfgGfuAfcUfuGfgUfcAfaGfaAf(invdT) AM01501-SS 969UfgGfuAfcUfuGfgUfcAfaGfaUfcAf(invdT) AM01502-SS 970GfgUfaCfuUfgGfuCfaAfgAfuCfgAf(invdT) AM01503-SS 971UfaCfuUfgGfuCfaAfgAfuCfgCfcAf(invdT) AM01504-SS 972CfuCfcUfaCfcGfcCfuUfcAfcGfaAf(invdT) AM01505-SS 973CfcUfaCfcGfcCfuUfcAfcGfaGfgAf(invdT) AM01506-SS 974CfuAfcCfgCfcUfuCfaCfgAfgGfgAf(invdT) AM01507-SS 975CfuGfaGfaCfaGfuGfcUfcUfgCfgAf(invdT) AM01508-SS 976AfgUfuCfgAfgGfgGfgCfuGfaAfgAf(invdT) AM01509-SS 977GfuUfcGfaGfgGfgGfcUfgAfaGfaAf(invdT) AM01510-SS 978UfcGfaGfgGfgGfcUfgAfaGfaAfuAf(invdT) AM01511-SS 979CfuCfuAfaCfgUfgCfaCfgGfaGfaAf(invdT) AM01512-SS 980CfuAfaCfgUfgCfaCfgGfaGfaCfgAf(invdT) AM01513-SS 981AfcGfuGfcAfcGfgAfgAfcGfcCfaAf(invdT) AM01613-SS 982(Chol-TEG)uAuAfgCfcCfaAfgAfaAfgUfgAfaAfgAf(invdT) AM01614-SS 983AfgCfcCfaAfgAfaAfgUfgAfaAfgUf(invdT) AM01615-SS 984(Chol-TEG)uAuGfcCfcAfaGfaAfaGfuGfaAfaGfaAf(invdT) AM01616-SS 985(Chol-TEG)uAuCfcCfaAfgAfaAfgUfgAfaAfgAfcAf(invdT) AM01617-SS 986(Chol-TEG)uAuCfcAfaGfaAfaGfuGfaAfaGfaCfcAf(invdT) AM01618-SS 987CfcAfaGfaAfaGfuGfaAfaGfaCfcUf(invdT) AM01619-SS 988(Chol-TEG)uAuCfaAfgAfaAfgUfgAfaAfgAfcCfaAf(invdT) AM01620-SS 989(Chol-TEG)uAuUfuUfgAfgCfcUfcAfgCfuUfcUfcAf(invdT) AM01905-SS 990(Chol-TEG)uAuCfcCfaAfgAfaAfgUfgAfaAfgAfscsAf(invdT) AM01908-SS 991(Chol-TEG)uAuCfcAfaGfaAfaGfuGfaAfaGfaCfscsAf(invdT) AM01911-SS 992(Chol-TEG)uAuUfuUfgAfgCfcUfcAfgCfuUfcUfscsAf(invdT) AM01922-SS 993(Chol-TEG)uAuCfcCfaAfgAfAfAfgUfgAfaAfgAfscsAf(invdT) AM01924-SS 994(Chol-TEG)uAuCfcAfaGfaAfAfGfuGfaAfaGfaCfscsAf(invdT) AM01926-SS 995(Chol-TEG)uAuUfuUfgAfgCfCfUfcAfgCfuUfcUfscsAf(invdT) AM01932-SS 996GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAfXuAu(TEG-Chol) AM01995-SS 997(Chol-TEG)uAuCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(invdT) AM02061-SS 998(Chol-TEG)uAuCfcCfaAfgAfAfAfgUfgAfaAfgAfcAf(invdT) AM02063-SS 999(Chol-TEG)uAuUfuUfgAfgCfCfUfcAfgCfuUfcUfcAf(invdT) AM02084-SS 1000(Alk-SS-C6)CfcAfaGfaAfaGfuGfaAfaGfaCfcAf(invdT) AM02085-SS 1001(NH2-C6)CfcAfaGfaAfaGfuGfaAfaGfaCfcAf(invdT) AM02168-SS 1002uAuAusGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-C6)(TEG- Chol) AM02169-SS1003 (Chol-TEG)uAuAusGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfscsAf AM02173-SS1004 usGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-C6)(TEG-Chol) AM02174-SS1005 GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-C6)(TEG-Chol) AM02196-SS1006 (Chol-TEG)uAuAusGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM02202-SS1007 GfsgsAfgCfcCfaAfGfAfaAfgUfgAfaAfgAf(C6-NH2) AM02203-SS 1008GfsasGfcCfcAfaGfAfAfaGfuGfaAfaGfaAf(C6-NH2) AM02204-SS 1009AfsgsCfcCfaAfgAfAfAfgUfgAfaAfgAfcAf(C6-NH2) AM02205-SS 1010GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-NH2) AM02206-SS 1011CfscsCfaAfgAfaAfGfUfgAfaAfgAfcCfaAf(C6-NH2) AM02207-SS 1012GfscsUfuUfgAfgCfCfUfcAfgCfuUfcUfcAf(C6-NH2) AM02209-SS 1013uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-NH2) AM02269-SS 1014GfsgsAfgCfcCfaAfGfAfaAfgUfgAfaAfgAf(C6-SS-Alk-Me) AM02270-SS 1015GfsasGfcCfcAfaGfAfAfaGfuGfaAfaGfaAf(C6-SS-Alk-Me) AM02271-SS 1016AfsgsCfcCfaAfgAfAfAfgUfgAfaAfgAfcAf(C6-SS-Alk-Me) AM02272-SS 1017GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-Alk-Me) AM02273-SS 1018CfscsCfaAfgAfaAfGfUfgAfaAfgAfcCfaAf(C6-SS-Alk-Me) AM02274-SS 1019GfscsUfuUfgAfgCfCfUfcAfgCfuUfcUfcAf(C6-SS-Alk-Me) AM02275-SS 1020uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-Alk-Me) AM02328-SS 1021uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(NAG3) AM02329-SS 1022uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-NAG3) AM02330-SS 1023(Chol-TEG)uAuAusGfscCfcAfaGfaAfaGfuGfaAfaGfaCfscsAf AM02351-SS 1024(Chol-TEG)uAuAusGfscCfcAfaGfaaAfGfuGfaAfaGfaCfscsAf AM02352-SS 1025(Chol-TEG)uAuAusGfscCfcAfaGfAfaAfGfuGfaAfaGfaCfscsAf AM02353-SS 1026(Chol-TEG)uAuAusgsCfcCfaAfgAfaAfGfuGfaAfaGfaCfscsAf AM02355-SS 1027(Chol-TEG)uAuAusGfscCfcAfaGfaAfaGfuGfA_(UNA)AfaGfaCfscsAf AM02356-SS1028 (Chol-TEG)uAuAusGfscCfcAfaGfaAfaGfuG_(UNA)aAfaGfaCfscsAf AM02357-SS1029 (Chol-TEG)uAuAusGfscCfcAfaGfaAfaGfU_(UNA)GfaAfaGfaCfscsAfAM02358-SS 1030 (Chol-TEG)uAuAusGfscCfcAfaGfaAfaG_(UNA)uGfaAfaGfaCfscsAfAM02359-SS 1031(Chol-TEG)uAuAusGfscCfcAfaGfaAfA_(UNA)GfuGfaAfaGfaCfscsAf AM02360-SS1032 (Chol-TEG)uAuAusGfscCfcAfaGfaA_(UNA)aGfuGfaAfaGfaCfscsAf AM02361-SS1033 (Chol-TEG)uAuAusGfscCfcAfaGfA_(UNA)AfaGfuGfaAfaGfaCfscsAfAM02362-SS 1034 (Chol-TEG)uAuAusGfscCfcAfaG_(UNA)aAfaGfuGfaAfaGfaCfscsAfAM02399-SS 1035 (Chol-TEG)uAuAusGfscUfuUfgAfgCfcUfcAfgCfuUfcUfscsAfAM02400-SS 1036 (Chol-TEG)uAuAusGfscUfuUfgAfgcCfUfcAfgCfuUfcUfscsAfAM02401-SS 1037 (Chol-TEG)uAuAusGfscUfuUfgAfGfcCfUfcAfgCfuUfcUfscsAfAM02402-SS 1038 (Chol-TEG)uAuAusgsCfuUfuGfaGfCfcUfcAfgCfuUfcUfscsAfAM02403-SS 1039 (NAG4)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA)AM02431-SS 1040 (Chol-TEG)uAuAusGfscCfcAfaGfaAfaGfuGfaAfaGfaCfc(invdA)AM02435-SS 1041(Chol-TEG)uAusasuGfaGfcCfcAfaGfaAfaGfuGfaAfaGfaCfc(invdA) AM02436-SS1042 (Chol-TEG)uAuAusGfscUfuUfgAfgCfcUfcAfgCfuUfcUfc(invdA) AM02440-SS1043 (Chol-TEG)uAusasuGfuGfcUfuUfgAfgCfcUfcAfgCfuUfcUfc(invdA)AM02457-SS 1044 GfscsUfuUfgAfgCfCfUfcAfgCfuUfcUfcAf(C6-SMPT-Alk)AM02458-SS 1045 uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SMPT-Alk)AM02459-SS 1046 uAuAusGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM02463-SS1047 uAuAusGfsuUfuGfgAfgCfcCfaAfgAfaAfgUfgAf(C6-NH2) AM02465-SS 1048uAuAusUfsuUfgGfaGfcCfcAfaGfaAfaGfuGfaAf(C6-NH2) AM02467-SS 1049uAuAusUfsuGfgAfgCfcCfaAfgAfaAfgUfgAfaAf(C6-NH2) AM02469-SS 1050uAuAusUfsgGfaGfcCfcAfaGfaAfaGfuGfaAfaAf(C6-NH2) AM02471-SS 1051uAuAusAfsaGfuGfcUfuUfgAfgCfcUfcAfgCfuAf(C6-NH2) AM02473-SS 1052uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C6-NH2) AM02475-SS 1053uAuAusGfsgCfuGfuGfgUfgAfcCfgCfaAfcAfaAf(C6-NH2) AM02477-SS 1054uAuAusCfsuGfuGfgUfgAfcCfgCfaAfcAfaGfcAf(C6-NH2) AM02479-SS 1055uAuAusUfsgUfgGfuGfaCfcGfcAfaCfaAfgCfcAf(C6-NH2) AM02490-SS 1056(Chol-TEG)uAuAusGfcCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02491-SS 1057(Chol-TEG)uAuAuGfcCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02494-SS 1058(Chol-TEG)uAuAusGfcCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM02495-SS 1059(Chol-TEG)uAuAuGfcCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM02496-SS 1060(Chol-TEG)uAuAusGfcCfcAfaGfAfaaGfuGfaAfaGfaCfc(invdA) AM02497-SS 1061(Chol-TEG)uAuAuGfcCfcAfaGfAfaaGfuGfaAfaGfaCfc(invdA) AM02498-SS 1062(Chol-TEG)uAuAusGfcCfcAfagAfAfaGfuGfaAfaGfaCfc(invdA) AM02499-SS 1063(Chol-TEG)uAuAuGfcCfcAfagAfAfaGfuGfaAfaGfaCfc(invdA) AM02500-SS 1064(Chol-TEG)uAuAusGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA) AM02501-SS 1065(Chol-TEG)uAuAuGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA) AM02513-SS 1066uAuAusGfsuUfuGfgAfgCfcCfaAfgAfaAfgUfgAf(C6-SS-Alk-Me) AM02514-SS 1067uAuAusUfsuUfgGfaGfcCfcAfaGfaAfaGfuGfaAf(C6-SS-Alk-Me) AM02515-SS 1068uAuAusUfsuGfgAfgCfcCfaAfgAfaAfgUfgAfaAf(C6-SS-Alk-Me) AM02516-SS 1069uAuAusUfsgGfaGfcCfcAfaGfaAfaGfuGfaAfaAf(C6-SS-Alk-Me) AM02517-SS 1070uAuAusAfsaGfuGfcUfuUfgAfgCfcUfcAfgCfuAf(C6-SS-Alk-Me) AM02518-SS 1071uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C6-SS-Alk-Me) AM02519-SS 1072uAuAusGfsgCfuGfuGfgUfgAfcCfgCfaAfcAfaAf(C6-SS-Alk-Me) AM02520-SS 1073uAuAusCfsuGfuGfgUfgAfcCfgCfaAfcAfaGfcAf(C6-SS-Alk-Me) AM02521-SS 1074uAuAusUfsgUfgGfuGfaCfcGfcAfaCfaAfgCfcAf(C6-SS-Alk-Me) AM02530-SS 1075(NH2-C6)GfcCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM02545-SS 1076(Chol-TEG)uAuAuGfscCfcAfaGfaAfaGfuGfaAfaGfaCfc(invdA) AM02550-SS 1077(Me-Alk-SS-C6)GfcCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3)AM02553-SS 1078(Chol-TEG)uAuAusGfcCfcAfaGfaAfA_(UNA)GfuGfaAfaGfaCfc(invdA) AM02554-SS1079 (Chol-TEG)uAuAusGfcCfcAfaGfaA_(UNA)aGfuGfaAfaGfaCfc(invdA)AM02555-SS 1080(Chol-TEG)uAuAusGfcCfcAfaGfA_(UNA)AfaGfuGfaAfaGfaCfc(invdA) AM02556-SS1081 (Chol-TEG)uAuAusGfcCfcAfaG_(UNA)aAfaGfuGfaAfaGfaCfc(invdA)AM02580-SS 1082 AfsgsCfcCfaAfgAfaAfgUfgAfaAfgAfcAf(C6-NH2) AM02581-SS1083 AfsgsCfcCfaAfgAfaAfgUfgAfaAfgAfcAf(C6-SS-Alk-Me) AM02583-SS 1084CfscsCfaAfgAfaagUfgAfaAfgAfcCfaAf(C6-NH2) AM02584-SS 1085CfscsCfaAfgAfaagUfgAfaAfgAfcCfaAf(C6-SS-Alk-Me) AM02634-SS 1086(Chol-TEG)UAUUAGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02635-SS 1087(Chol-TEG)UfaUfaAGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02636-SS 1088(Chol-TEG)uauaAGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02637-SS 1089(Chol-TEG)AUAUUGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02638-SS 1090(Chol-TEG)AfuAfuUGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02639-SS 1091(Chol-TEG)auauUGfscCfcAfaGfaaAfGfuGfaAfaGfaCfc(invdA) AM02649-SS 1092CfcAfaGfaAfaGfuGfaAfaGfaCfcAfuAu(TEG-Chol) AM02651-SS 1093gscsCfcAfagaAfAfGfugaAfagaCfcAf(C6-NH2) AM02652-SS 1094gscsCfcAfagaAfAfGfugaAfagaCfcAf(C6-SS-Alk-Me) AM02653-SS 1095uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM02654-SS 1096(DBCO-TEG)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM02655-SS 1097 uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3)AM02663-SS 1098 uAuAusgsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3)AM02664-SS 1099 uAuAusGfsugcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3)AM02665-SS 1100 uAuAusgsugcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3)AM02666-SS 1101(DBCO-TEG)uAuAusgsugcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3- NAG3)AM02723-SS 1102 usGfsgAfgCfcCfaAfgAfaAfgUfg(invdA) AM02724-SS 1103gsGfsaGfcCfcAfaGfaAfaGfuGfa(invdA) AM02725-SS 1104gsAfsgCfcCfaAfgAfaAfgUfgAfa(invdA) AM02726-SS 1105asGfscCfcAfaGfaAfaGfuGfaAfa(invdA) AM02727-SS 1106gsCfscCfaAfgAfaAfgUfgAfaAfg(invdA) AM02728-SS 1107csCfscAfaGfaAfaGfuGfaAfaGfa(invdA) AM02729-SS 1108csCfsaAfgAfaAfgUfgAfaAfgAfc(invdA) AM02730-SS 1109csAfsaGfaAfaGfuGfaAfaGfaCfc(invdA) AM02731-SS 1110asAfsgAfaAfgUfgAfaAfgAfcCfa(invdA) AM02732-SS 1111usGfscUfuUfgAfgCfcUfcAfgCfu(invdA) AM02733-SS 1112csUfsuUfgAfgCfcUfcAfgCfuUfc(invdA) AM02734-SS 1113usUfsgAfgCfcUfcAfgCfuUfcUfc(invdA) AM02735-SS 1114usGfsuGfgUfgAfcCfgCfaAfcAfa(invdA) AM02736-SS 1115gsUfsgGfuGfaCfcGfcAfaCfaAfg(invdA) AM02737-SS 1116usGfsgUfgAfcCfgCfaAfcAfaGfc(invdA) AM02738-SS 1117gsGfsuGfaCfcGfcAfaCfaAfgCfc(invdA) AM02739-SS 1118GfsgsAfgCfcCfaAfgAfaAfgUfg(invdA) AM02740-SS 1119GfsasGfcCfcAfaGfaAfaGfuGfa(invdA) AM02741-SS 1120AfsgsCfcCfaAfgAfaAfgUfgAfa(invdA) AM02742-SS 1121GfscsCfcAfaGfaAfaGfuGfaAfa(invdA) AM02743-SS 1122CfscsCfaAfgAfaAfgUfgAfaAfg(invdA) AM02744-SS 1123CfscsAfaGfaAfaGfuGfaAfaGfa(invdA) AM02745-SS 1124CfsasAfgAfaAfgUfgAfaAfgAfc(invdA) AM02746-SS 1125AfsasGfaAfaGfuGfaAfaGfaCfc(invdA) AM02747-SS 1126AfsgsAfaAfgUfgAfaAfgAfcCfa(invdA) AM02748-SS 1127GfscsUfuUfgAfgCfcUfcAfgCfu(invdA) AM02749-SS 1128UfsusUfgAfgCfcUfcAfgCfuUfc(invdA) AM02750-SS 1129UfsgsAfgCfcUfcAfgCfuUfcUfc(invdA) AM02751-SS 1130GfsusGfgUfgAfcCfgCfaAfcAfa(invdA) AM02752-SS 1131UfsgsGfuGfaCfcGfcAfaCfaAfg(invdA) AM02753-SS 1132GfsgsUfgAfcCfgCfaAfcAfaGfc(invdA) AM02754-SS 1133GfsusGfaCfcGfcAfaCfaAfgCfc(invdA) AM02842-SS 1134(NH2-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM02843-SS 1135 (NH2-C6)uAuAusgsugcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3) AM02844-SS 1136(Alk-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM02845-SS 1137 (Alk-C6)uAuAusgsugcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3) AM02867-SS 1138(Spermine)uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11- PEG3-NAG3)AM02868-SS 1139(Spermine)(Spermine)uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3) AM02869-SS 1140(Spermine)(Spermine)(Spermine)uAuAusGfsuGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3) AM02872-SS 1141uAuAusGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA) AM02954-SS 1142uAuAugscsCfcAfagaAfAfGfugaAfagaCfcAf(C6-NH2) AM02955-SS 1143uAuAugscsCfcAfagaAfAfGfugaAfagaCfcAf(C6-SS-Alk-Me) AM02956-SS 1144uAuAugscsCfcAfagaAfAfGfugaAfagaCfcAf(C11-PEG3-NAG3) AM02960-SS 1145uAuAugscsccaagaaAfGfugaaagacca(C11-PEG3-NAG3) AM02961-SS 1146uAuAugscsccaagaAfaGfugaaagacca(C11-PEG3-NAG3) AM02974-SS 1147(Stearyl)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM03028-SS 1148 (Chol-TEG)AuAusGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA)AM03029-SS 1149 (Chol-TEG)uAusGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA)AM03031-SS 1150 (BCN)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03032-SS 1151uaUfauGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03033-SS 1152(Me-Alk-SS- C6)uaUfauGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3)AM03034-SS 1153 (NH2-C6)uaUfauGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03035-SS 1154AuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03044-SS 1155(Norbornene- C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3)AM03045-SS 1156(Alk-BC9-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM03046-SS 1157 uAuAugscsCfcAfagaAfAfGfugaAfagaCfcAf(C6-NAG3) AM03052-SS1158 (NH2-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03053-SS1159 (NH2-Ser)(NH2-Ser)(NH2-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03054-SS 1160(Norbornene- Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA)AM03055-SS 1161 (Norbornene-Ser)(Norbornene-Ser)(Norbornene-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03056-SS 1162(NH2-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03057-SS 1163(Norbornene- C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03071-SS1164 GfsgsAfgCfcCfaAfgAfaAfgUfgAf(C11-PEG3-NAG3) AM03072-SS 1165CfscsCfaAfgAfaAfgUfgAfaAfgAf(C11-PEG3-NAG3) AM03073-SS 1166AfsasGfaAfaGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03074-SS 1167AfsgsAfaAfgUfgAfaAfgAfcCfaAf(C11-PEG3-NAG3) AM03083-SS 1168(Spermine)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM03084-SS 1169(Spermine)(Spermine)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03085-SS 1170(Spermine)(Spermine)(Spermine)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03086-SS 1171(NH2-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-NH2) AM03112-SS 1172uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfCMAM(C11-PEG3-NAG3) AM03113-SS 1173uAuAU_(UNA)GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03114-SS1174 (Spermine)GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3)AM03115-SS 1175(Spermine)(Spermine)(Spermine)GfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03117-SS 1176(Alk-C6-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM03118-SS 1177 (Alk-PEG4-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3) AM03132-SS1178 uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-NAG3) AM03133-SS 1179uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-PEG4-NAG3) AM03135-SS 1180(C6-PEG4- NAG3)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03136-SS1181 uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfauAu(C6-NH2) AM03137-SS 1182uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfauAu(C6-PEG4-NAG3) AM03138-SS 1183(TetZ-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11- PEG3-NAG3)AM03139-SS 1184 (Alk-PEG5-C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3) AM03140-SS1185 (Alk-NHCO- C6)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03141-SS 1186 (Alk-NHCO-SS-C6)uaUfauGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3- NAG3) AM03142-SS1187 uAuAusGfscCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03143-SS1188 uAuAuGfsusGfcUfuUfgAfgCfcUfcAfgCfuUfcAf(C11-PEG3-NAG3) AM03145-SS1189 (NH2-C6)(NH2- Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA)AM03146-SS 1190 (NH2-C6)(NH2-Ser)(NH2-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03147-SS 1191(NH2-C6)(NH2-Ser)(NH2-Ser)(NH2-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03152-SS 1192uAuAugscsccaagaaaGfuGfaaagacca(C11-PEG3-NAG3) AM03153-SS 1193uAuAugscsccaagaaaGfugaaagacca(C11-PEG3-NAG3) AM03177-SS 1194uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-C12-NAG3) AM03178-SS 1195uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C11-palm-NAG3) AM03179-SS 1196uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-C6)(C11- palm-NAG3)AM03180-SS 1197 uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfauAu(C11-palm-NAG3)AM03181-SS 1198 (Alk-C6-C6)(Alk-C6-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03182-SS 1199(Alk-C6-C6)(Alk-C6-Ser)(Alk-C6-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03183-SS 1200(Alk-C6-C6)(Alk-C6-Ser)(Alk-C6-Ser)(Alk-C6-Ser)uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfc(invdA) AM03209-SS 1201uaUfaugscsccaagaAfaGfugaaagacca(C11-PEG3-NAG3) AM03210-SS 1202uauaugscsccaagaAfaGfugaaagacca(C11-PEG3-NAG3) AM03213-SS 1203udAudAugscsccaagaAfaGfugaaagacca(C11-PEG3-NAG3) AM03214-SS 1204uAugscsccaagaAfaGfugaaagaccuAu(C11-PEG3-NAG3) AM03217-SS 1205uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-C6-NAG3) AM03218-SS 1206uAuAuGfscsCfcAfaGfaAfAfGfuGfaAfaGfaCfcAf(C6-SS-C6)(C11- PEG3-NAG3)AM03327-SS 1207 uAuAugscsccaagaaAfGfugaaagacCMAM(C11-PEG3-NAG3)AM03328-SS 1208 uAuAugscsccaagaaAfGfugaaagacca(C6-NH2) AM03329-SS 1209uAuAugscsccaagaaAfGfugaaagacca(C6-NAG3) AM03338-SS 1210uAuAugscsccaagaaAfGfugaaagacca(NH2-C7) AM03339-SS 1211uAuAugscsccaagaaAfGfugaaagacca(NAG13) AM03354-SS 1212cscscaAfgAfaagugaaaga(C11-PEG3-NAG3) AM03355-SS 1213cscscaaGfAfaagugaaaga(C11-PEG3-NAG3) AM03356-SS 1214CfscsCfaAfgAfaAfgUfgAfaAfGMAM(C11-PEG3-NAG3) AM03357-SS 1215CMsCMsCfaAfgAfaAfgUfgAfaAfGMAM(C11-PEG3-NAG3) AM03358-SS 1216CMsCMsCfaAfgAfaAfgUfgAfaAfgAf(C11-PEG3-NAG3) AM03360-SS 1217asasgaAfaGfugaaagacca(C11-PEG3-NAG3) AM03361-SS 1218asasgaaAfGfugaaagacca(C11-PEG3-NAG3) AM03362-SS 1219AfsasGfaAfaGfuGfaAfaGfaCfCMAM(C11-PEG3-NAG3) AM03363-SS 1220AMsAMsGfaAfaGfuGfaAfaGfaCfCMAM(C11-PEG3-NAG3) AM03364-SS 1221AMsAMsGfaAfaGfuGfaAfaGfaCfcAf(C11-PEG3-NAG3) AM03369-SS 1222(NH2-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03370-SS 1223(NH2-C6)(NH2-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03371-SS 1224(NH2-C6)(NH2-Ser)(NH2-Ser)(NH2- Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA)AM03372-SS 1225 (Alk-C6-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA)AM03373-SS 1226 (Alk-C6-C6)(Alk-C6-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03374-SS 1227(Alk-C6-C6)(Alk-C6-Ser)3(Alk-C6-Ser)(Alk-C6-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03398-SS 1228(Chol-TEG)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03399-SS 1229(Chol-TEG)uAuAugscsccaagaAfaGfugaaagacca AM03400-SS 1230(NH2-Ser)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03401-SS 1231(Alk-C6-Ser)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03402-SS 1232uAuAugscsccaagaAfaGfugaaagacca(NAG13) AM03403-SS 1233uAuAugscsccaagaAfAfGfugaaagacca(NAG13) AM03404-SS 1234uAuAugscsccaagaAfAfgugaaagacca(NAG13) AM03405-SS 1235uAuAugscsccaagaaaGfUfgaaagacca(NAG13) AM03406-SS 1236uAuAugscsccaagaAfaGfugaaagacCMAM(NAG13) AM03407-SS 1237uAugscsccaagaAfaGfugaaagaccaAu(NAG13) AM03408-SS 1238uAugscsccaagaAfaGfugaaagaccuAu(NAG13) AM03409-SS 1239uaugscsccaagaAfaGfugaaagaccuAu(NAG13) AM03411-SS 1240uAuAusgscccaagaAfaGfugaaagacca(NAG13) AM03412-SS 1241uAuAsusgcccaagaAfaGfugaaagacca(NAG13) AM03413-SS 1242uAuAugscccaagaAfaGfugaaagacca(NAG13) AM03414-SS 1243uAuAugcsccaagaAfaGfugaaagacca(NAG13) AM03420-SS 1244(NH2-C6)(NH2-Ser)uAugscsccaagaAfaGfugaaagaccuAu(Ser- NH2)(C6-NH2)AM03421-SS 1245 (Alk-C6-C6)(Alk-C6-Ser)uAugscsccaagaAfaGfugaaagaccuAu(Ser-C6-Alk)(C6-C6-Alk) AM03422-SS1246 (NH2-C6)uAugscsccaagaAfaGfugaaagaccuAu(C6-NH2) AM03423-SS 1247(Alk-C6-C6)uAugscsccaagaAfaGfugaaagaccuAu(C6-C6-Alk) AM03428-SS 1248uAugscsccaagaAfaGfugaaagaccsusAu(NAG13) AM03429-SS 1249uAugscsccaagaAfaGfugaaagacc(invdA)Au(NAG13) AM03430-SS 1250uAugscsccaagaAfaGfugaaagacCMAMAu(NAG13) AM03431-SS 1251(NH2-C6)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03432-SS 1252(Alk-C6-C6)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03433-SS 1253(NH2-C6)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03434-SS 1254(Alk-C6-C6)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03435-SS 1255(Alk-PEG5-Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03436-SS 1256(Alk-PEG5-C6)(Alk-PEG5- Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA)AM03437-SS 1257 (Alk-PEG5-Ser)uauaugscsccaagaAfaGfugaaagacc(invdA)AM03438-SS 1258 (Alk-PEG5-C6)uAuAugscsccaagaAfaGfugaaagacc(invdA)AM03439-SS 1259 (Alk-PEG5-C6)uauaugscsccaagaAfaGfugaaagacc(invdA)AM03440-SS 1260 (Alk-PEG5-C6)uAugscsccaagaAfaGfugaaagaccuAu(C6-PEG5-Alk)AM03456-SS 1261 uAuAugscsccaagaAfaGfugaaagaccA_(LNA)(NAG13) AM03463-SS1262 uAuAuG_(LNA)scsccaagaAfaGfugaaagaccA_(LNA)(NAG13) AM03464-SS 1263uAuAuG_(LNA)scsccaagaAfaGfugaaagacca(NAG13) AM03476-SS 1264uAugscsccaagaAfaGfugaaagaccuau(NAG13) AM03477-SS 1265uAugscsccaagaAfaGfugaaagaccudAu(NAG13) AM03478-SS 1266uAugscsccaagaAfaGfugaaagaccaau(NAG13) AM03479-SS 1267uAugscsccaagaAfaGfugaaagaccauu(NAG13) AM03480-SS 1268uAugscsccaagaAfaGfugaaagaccaua(NAG13) AM03481-SS 1269uAugscsccaagaAfaGfugaaagaccaUu(NAG13) AM03482-SS 1270uAugscsccaagaAfaGfugaaagaccaUa(NAG13) AM03520-SS 1271uAuAuG_(LNA)csccaagaAfaGfugaaagacca(NAG13) AM03521-SS 1272uAuAuG_(LNA)csccaagaAfaGfugaaagaccA_(LNA)(NAG13) AM03540-SS 1273(Alk-PEG13-C6)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03541-SS 1274(Alk-PEG13-C6)(Alk-PEG13- Ser)uAuAugscsccaagaAfaGfugaaagacc(invdA)AM03570-SS 1275 (NH2-C6)uuAgagscsccaagaAfaGfugaaagacc(invdA) AM03571-SS1276 (Alk-C6-C6)uuAgagscsccaagaAfaGfugaaagacc(invdA) AM03572-SS 1277(NH2-C6)uuAuugscsccaagaAfaGfugaaagacc(invdA) AM03573-SS 1278(Alk-C6-C6)uuAuugscsccaagaAfaGfugaaagacc(invdA) AM03574-SS 1279(NH2-C6)uuGAugscsccaagaAfaGfugaaagacc(invdA) AM03575-SS 1280(Alk-C6-C6)uuGAugscsccaagaAfaGfugaaagacc(invdA) AM03576-SS 1281(NH2-C6)uuagagscsccaagaAfaGfugaaagacc(invdA) AM03577-SS 1282(Alk-C6-C6)uuagagscsccaagaAfaGfugaaagacc(invdA) AM03578-SS 1283(NH2-C6)uAugagscsccaagaAfaGfugaaagacc(invdA) AM03579-SS 1284(Alk-C6-C6)uAugagscsccaagaAfaGfugaaagacc(invdA) AM03582-SS 1285uAuAugscsccaagaAfaGfugaaagacca(C6-NH2) AM03583-SS 1286uAugscsccaagaAfaGfugaaagaccuAu(C6-NH2) AM03586-SS 1287(Chol-TEG)aUaGasGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA) AM03587-SS 1288(Chol-TEG)uauausGfcCfcAfAfgaAfaGfuGfaAfaGfaCfc(invdA) AM03588-SS 1289uAuAugscsccaagaAfaGfugaaagacca(NAG14) AM03591-SS 1290AugscsccaagaAfaGfugaaagaccuAuu(NAG13) AM03592-SS 1291AugscsccaagaAfaGfugaaagaccuGAu(NAG13) AM03628-SS 1292uAuAugscsccaagaAfaGfugaaagacca(NAG15) AM03629-SS 1293uAuAugscsccaagaAfaGfugaaagacca(NAG16) AM03630-SS 1294uAuAugscsccaagaAfaGfugaaagacca(NAG17) AM03631-SS 1295(NAG18)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03632-SS 1296(NAG18)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03633-SS 1297uAuAugscsccaagaAfaGfugaaagacca(NAG18) AM03634-SS 1298uAugscsccaagaAfaGfugaaagaccuAu(NAG18) AM03635-SS 1299(NAG19)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03636-SS 1300(NAG19)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03637-SS 1301uAuAugscsccaagaAfaGfugaaagacca(NAG19) AM03638-SS 1302uAugscsccaagaAfaGfugaaagaccuAu(NAG19) AM03639-SS 1303(NAG20)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03640-SS 1304(NAG20)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03641-SS 1305uAuAugscsccaagaAfaGfugaaagacca(NAG20) AM03642-SS 1306uAugscsccaagaAfaGfugaaagaccuAu(NAG20) AM03653-SS 1359uauaugscsccaagaAfaGfugaaagacca(NAG13) AM03654-SS 1360udAudAugscsccaagaAfaGfugaaagacca(NAG13) AM03669-SS 1361uAuAugscsccaagaAfaGfugaaagacc(invdA)(NAG13) AM03684-SS 1362uAuAugscsccaagaAfaGfugaaagacca AM03703-SS 1363(NAG21)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03704-SS 1364(NAG21)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03705-SS 1357gagscsccaagaAfaGfugaaagaccuAuu(NAG13) AM03706-SS 1358gagscsccaagaAfaGfugaaagaccuGAu(NAG13) AM03726-SS 1351cscscaAfgAfaagugaaaga(NAG13) AM03727-SS 1352XscsccaAfgAfaagugaaaga(NAG13) AM03728-SS 1353XsXscccaAfgAfaagugaaaga(NAG13) AM03729-SS 1354CMsCMscaAfgAfaagugaaaGMAM(NAG13) AM03730-SS 1355cscscaAfgAfaagugaaaGMAM(NAG13) AM03731-SS 1356cscscaAfgAfaagugaaagu(NAG13) AM03738-SS 1365(NAG23)uAuAugscsccaagaAfaGfugaaagacc(invdA) AM03739-SS 1366(NAG23)uauaugscsccaagaAfaGfugaaagacc(invdA) AM03775-SS 1367udAuaugscsccaagaAfaGfugaaagacca(NAG13) AM03776-SS 1374udAugagscsccaagaAfaGfugaaagacca(NAG13) AM03777-SS 1349adTagagscsccaagaAfaGfugaaagacca(NAG13) AM03778-SS 1350auagagscsccaagaAfaGfugaaagacca(NAG13) AM03779-SS 1368uauaugscsccaagaAfaGfugaaagacc(invdA)(NAG13) AM03780-SS 1369u(invdA)uaugscsccaagaAfaGfugaaagacca(NAG13) AM03781-SS 1373udAuaugscsccaagaAfaGfugaaagaccu(NAG13) AM03782-SS 1370udAuaugscsccaagaAfaGfugaaagacc(invdA)(NAG13) AM03783-SS 1371udAuaugscsccaagaAfaGfugaaagacc(inva)(NAG13) AM03784-SS 1372udAuaugscsccaagaAfaGfugaaagacc(3′OMea)(NAG13) AM03800-SS 2206gacaugscsccaagaAfaGfugaaagacca(NAG13) AM03801-SS 2207ugaaugscsccaagaAfaGfugaaagacca(NAG13) AM03802-SS 2208gcgaugscsccaagaAfaGfugaaagacca(NAG13) AM03806-SS 2209uaugagscsccaagaAfaGfugaaagacca(NAG13) AM03807-SS 2210uuggagscsccaagaAfaGfugaaagacca(NAG13) AM03812-SS 2211cscscaAfgAfaagugaaagA_(LNA)(NAG13) AM03813-SS 2212cscscaAfgAfaagugaaaG_(LNA)a(NAG13) AM03814-SS 2213csmC_(LNA)scaAfgAfaagugaaaga(NAG13) AM03815-SS 2214mC_(LNA)scscaAfgAfaagugaaaga(NAG13) AM03816-SS 2215cscscaAfgAfaagugaaaG_(LNA)A_(LNA)(NAG13) AM03817-SS 2216mC_(LNA)smC_(LNA)scaAfgAfaagugaaaga(NAG13) AM03818-SS 2217mC_(LNA)scscaAfgAfaagugaaagA_(LNA)(NAG13) AM03834-SS 2218CfscsCfaAfgAfaAfgUfgAfaAfGMAM(NAG13) AM03836-SS 2219(NAG18)uaugagscsccaagaAfaGfugaaagacc(invdA) AM03838-SS 2220(NAG18)auagagscsccaagaAfaGfugaaagacc(invdA) AM03840-SS 2221(NAG18)gacaugscsccaagaAfaGfugaaagacc(invdA) AM03842-SS 2222(NAG18)ugaaugscsccaagaAfaGfugaaagacc(invdA) AM03844-SS 2223(NAG18)gcgaugscsccaagaAfaGfugaaagacc(invdA) AM03846-SS 2224(NAG18)uauaugcccaagaAfaGfugaaagacc(invdA) AM03848-SS 2225(NAG18)uauaugcccaagaAfaGfugaaagacCM(invdA) AM03850-SS 2226(NAG18)uauaugcccaagaAfaGfugaaagaCMCM(invdA) AM03886-SS 2227(Alk-PEG4-C6)uauaugscsccaagaAfaGfugaaagacca(NAG13) 1940UfgGfaGfuCfaAfcAfcUfuUfcGfaAfdT 1941 GfgAfgUfcAfaCfaCfuUfuCfgAfuAfdT1942 CfcCfaAfgGfaGfcAfuAfaGfuAfcAfdT 1943CfcAfaGfgAfgCfaUfaAfgUfaCfaAfdT 1944 CfaAfgGfaGfcAfuAfaGfuAfcAfaAfdT1945 AfgCfaUfaAfgUfaCfaAfaGfcUfgAfdT 1946UfgAfaGfaGfcAfcAfcAfgUfcGfuAfdT 1947 GfaAfgAfgCfaCfaCfaGfuCfgUfuAfdT1948 AfaGfaGfcAfcAfcAfgUfcGfuUfcAfdT 1949CfaCfaGfuCfgUfuCfuCfaCfuGfuAfdT 1950 CfaGfuCfgUfuCfuCfaCfuGfuCfaAfdT1951 GfcUfgUfaCfcAfcAfaAfuGfuAfcAfdT 1952CfuGfuAfcCfaCfaAfaUfgUfaCfcAfdT 1953 UfgUfaCfcAfcAfaAfuGfuAfcCfcAfdT1954 CfcAfcAfaAfuGfuAfcCfcAfcAfaAfdT 1955AfgAfuGfcCfaGfuGfcAfaGfgGfuAfdT 1956 GfgGfgUfcGfcUfgCfcUfaGfaGfgAfdT1957 GfcUfgCfuAfuGfaUfgGfcCfgCfgAfdT 1958CfuGfcUfaUfgAfuGfgCfcGfcGfgAfdT 1959 UfgGfcCfgCfgGfgCfuCfaGfcUfaAfdT1960 CfcGfcGfgGfcUfcAfgCfuAfcCfgAfdT 1961GfaCfcAfcGfcUfcUfcGfgGfuGfcAfdT 1962 AfcCfaCfgCfuCfuCfgGfgUfgCfgAfdT1963 CfcAfcGfcUfcUfcGfgGfuGfcGfcAfdT 1964AfaGfcGfcGfgAfaCfuGfgGfgAfcAfdT 1965 GfgAfcUfgGfgCfgGfcCfaCfgCfcAfdT1966 GfcCfgGfaAfcCfcGfgAfcAfaCfgAfdT 1967CfgGfaAfcCfcGfgAfcAfaCfgAfcAfdT 1968 GfgAfaCfcCfgGfaCfaAfcGfaCfaAfdT1969 GfaAfcCfcGfgAfcAfaCfgAfcAfuAfdT 1970CfcGfgAfcAfaCfgAfcAfuCfcGfcAfdT 1971 AfcAfaCfgAfcAfuCfcGfcCfcGfuAfdT1972 CfaAfcGfaCfaUfcCfgCfcCfgUfgAfdT 1973AfaCfgAfcAfuCfcGfcCfcGfuGfgAfdT 1974 AfcGfaCfaUfcCfgCfcCfgUfgGfuAfdT1975 CfaUfcCfgCfcCfgUfgGfuGfcUfuAfdT 1976AfuCfcGfcCfcGfuGfgUfgCfuUfcAfdT 1977 CfcGfcCfcGfuGfgUfgCfuUfcGfuAfdT1978 GfcCfcGfuGfgUfgCfuUfcGfuGfcAfdT 1979CfuUfcAfuGfuCfcCfaCfuCfaUfgAfdT 1980 GfcAfgCfcGfgCfaCfcGfcCfgAfaAfdT1981 GfgCfuCfcGfcAfaGfaGfuCfuGfuAfdT 1982GfcUfcCfgCfaAfgAfgUfcUfgUfcAfdT 1983 GfaGfuCfuGfuCfuUfcGfaUfgAfcAfdT1984 AfgUfcUfgUfcUfuCfgAfuGfaCfcAfdT 1985GfuCfuUfcGfaUfgAfcCfcGfcGfuAfdT 1986 UfcUfuCfgAfuGfaCfcCfgCfgUfcAfdT1987 CfuUfcGfaUfgAfcCfcGfcGfuCfgAfdT 1988UfuCfgAfuGfaCfcCfgCfgUfcGfuAfdT 1989 UfcGfaUfgAfcCfcGfcGfuCfgUfuAfdT1990 CfgAfuGfaCfcCfgCfgUfcGfuUfgAfdT 1991GfaUfgAfcCfcGfcGfuCfgUfuGfgAfdT 1992 UfgAfcCfcGfcGfuCfgUfuGfgCfgAfdT1993 GfaCfcCfgCfgUfcGfuUfgGfcGfgAfdT 1994GfcUfgGfuGfgCfgCfuAfcGfcGfgAfdT 1995 UfgGfuGfgCfgCfuAfcGfcGfgGfgAfdT1996 GfgUfgGfcGfcUfaCfgCfgGfgGfcAfdT 1997GfuGfgCfgCfuAfcGfcGfgGfgCfgAfdT 1998 GfcUfaCfgCfgGfgGfcGfcAfcCfcAfdT1999 GfgCfgCfaCfcCfcUfaCfaUfcGfcAfdT 2000CfaCfcCfcUfaCfaUfcGfcCfgCfgAfdT 2001 CfcCfcUfaCfaUfcGfcCfgCfgCfuAfdT2002 CfcCfuAfcAfuCfgCfcGfcGfcUfgAfdT 2003CfcUfaCfaUfcGfcCfgCfgCfuGfuAfdT 2004 CfuAfcAfuCfgCfcGfcGfcUfgUfaAfdT2005 UfaCfaUfcGfcCfgCfgCfuGfuAfcAfdT 2006CfaUfcGfcCfgCfgCfuGfuAfcUfgAfdT 2007 UfcGfcCfgCfgCfuGfuAfcUfgGfgAfdT2008 CfuGfcGfcCfgGfcAfgCfcUfcAfuAfdT 2009GfcAfcCfcGfaGfgAfuCfuGfaCfgAfdT 2010 CfaCfcCfgAfgGfaUfcUfgAfcGfgAfdT2011 UfuGfcAfcGfaGfgCfcUfuCfuCfgAfdT 2012UfgCfaCfgAfgGfcCfuUfcUfcGfcAfdT 2013 GfcAfcGfaCfcUfgGfcUfcUfgUfuAfdT2014 GfcUfcUfgUfuGfcGfcCfuUfcAfgAfdT 2015UfuGfcGfcCfuUfcAfgGfaGfgAfuAfdT 2016 GfgAfcGfgCfaGfcUfgCfgCfgCfuAfdT2017 CfgCfgCfuCfcUfgUfcGfcCfuUfaAfdT 2018GfcGfcUfcCfuGfuCfgCfcUfuAfcAfdT 2019 CfgCfuCfcUfgUfcGfcCfuUfaCfgAfdT2020 GfcUfcCfuGfuCfgCfcUfuAfcGfuAfdT 2021CfuCfcUfgUfcGfcCfuUfaCfgUfuAfdT 2022 UfcCfuGfuCfgCfcUfuAfcGfuUfcAfdT2023 UfgUfcGfcCfuUfaCfgUfuCfaGfcAfdT 2024GfuCfgCfcUfuAfcGfuUfcAfgCfcAfdT 2025 UfcGfcCfuUfaCfgUfuCfaGfcCfgAfdT2026 CfgCfcUfuAfcGfuUfcAfgCfcGfgAfdT 2027GfcCfuUfaCfgUfuCfaGfcCfgGfuAfdT 2028 CfuUfaCfgUfuCfaGfcCfgGfuGfuAfdT2029 AfcGfuUfcAfgCfcGfgUfgUfgCfcAfdT 2030GfgUfgUfgCfcUfgCfcAfaGfcGfgAfdT 2031 GfcCfaCfcAfgUfuCfgAfgGfgGfgAfdT2032 CfaCfcAfgUfuCfgAfgGfgGfgCfgAfdT 2033UfcGfaGfgGfgGfcGfgAfgGfaAfuAfdT 2034 CfuGfcGfcAfgGfgUfuCfcUfcGfaAfdT2035 UfgCfgCfaGfgGfuUfcCfuCfgAfgAfdT 2036GfcGfcAfgGfgUfuCfcUfcGfaGfgAfdT 2037 UfuCfcUfcGfaGfgGfcGfgCfaCfcAfdT2038 CfuCfgAfgGfgCfgGfcAfcCfgAfuAfdT 2039UfcGfaGfgGfcGfgCfaCfcGfaUfgAfdT 2040 CfaGfaGfcGfcCfgGfcUfcAfcCfcAfdT2041 AfuCfaGfcUfgGfgGfaUfcGfgGfcAfdT 2042GfaUfcGfgGfcUfgUfgGfuGfaCfcAfdT 2043 CfcGfcAfaCfaAfgCfcAfgGfcGfuAfdT2044 GfcAfaCfaAfgCfcAfgGfcGfuCfuAfdT 2045AfgGfcGfuCfuAfcAfcCfgAfuGfuAfdT 2046 GfgCfgUfcUfaCfaCfcGfaUfgUfgAfdT2047 GfcGfuCfuAfcAfcCfgAfuGfuGfgAfdT 2048CfuGfgAfuCfcGfgGfaGfcAfcAfcAfdT 2049 CfuGfaUfuGfcUfcAfgGfgAfcUfcAfdT2050 AfuUfgCfuCfaGfgGfaCfuCfaUfcAfdT 2051AfgGfaAfcUfcAfaUfaAfaGfuGfcAfdT 2052 GfgAfaCfuCfaAfuAfaAfgUfgCfuAfdT

A sense strand containing a sequence listed in Table 1 or 3 can behybridized to any antisense strand containing a sequence listed in Table1 or 2 provided the two sequences have a region of at least 90%complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotidesequence; representative sequences are exemplified by the Duplex ID Nos.shown in Table 24. In some embodiments an F12 RNAi trigger consists ofany of the Duplex ID Nos. presented herein. In some embodiments an F12RNAi trigger comprises of any of the Duplex ID Nos. presented herein. Insome embodiments, an F12 RNAi trigger comprises the sense strand andantisense strand nucleotide sequences of any of the Duplex ID Nos.presented herein. In some embodiments, an F12 RNAi trigger comprises thesense strand and antisense strand nucleotide sequences of any of theDuplex ID Nos. presented herein and a targeting group and/or linkinggroup wherein the targeting group and/or linking group is covalentlylinked to the sense strand or the antisense strand. In some embodiments,an F12 RNAi trigger comprises the sense strand and antisense strandmodified nucleotide sequences of any of the Duplex ID Nos. presentedherein. In some embodiments, an F12 RNAi trigger comprises the sensestrand and antisense strand modified nucleotide sequences of any of theDuplex ID Nos. presented herein and a targeting group and/or linkinggroup wherein the targeting group and/or linking group is covalentlylinked to the sense strand or the antisense strand. In some embodiments,a F12 RNAi trigger comprises Duplex ID Nos. AD00900, AD01001, AD01520,AD02639, AD02640, AD02023, AD02642, AD02708, AD02807, AD02822, AD02867,or AD02868. In some embodiments, a F12 RNAi trigger comprises SEQ ID No.11, SEQ ID No. 150, or SEQ ID No. 177. In some embodiments, a F12 RNAitrigger comprises SEQ ID No 374 or SEQ ID No. 379.

In some embodiments, an F12 RNAi trigger further includes a targetinggroup, linking group, delivery polymer and/or other non-nucleotide groupcovalently linked to the 3′ and/or 5′ end of either the sense strandand/or the antisense strand. In some embodiments, an F12 RNAi triggercan contain a targeting group, linking group, delivery polymer, or othernon-nucleotide group covalently linked to the 3′ and/or 5′ end of thesense strand. In some embodiments a targeting group, linking group,delivery polymer, or other non-nucleotide group is linked to the 5′ endof an F12 RNAi trigger sense strand. In some embodiments, the targetinggroup, linking group, and/or delivery vehicle is linked directly orindirectly to the trigger via a linker/linking group. In someembodiments, a targeting group or delivery vehicle is linked to thetrigger via a labile, cleavable, or reversible bond or linker. Examplesof targeting groups and linking groups are provided in Table 4. Table 4provides several embodiments of F12 RNAi trigger sense strands having atargeting group or linking group linked to the 5′ or 3′ end.

A targeting group can enhance the pharmacokinetic or biodistributionproperties of an RNAi trigger or conjugate to which it is attached toimprove cell- or tissue-specific distribution and cell-specific uptakeof the conjugate. In some instances, binding of a targeting group to acell or cell receptor may initiate endocytosis. A targeting group can bemonovalent, divalent, trivalent, tetravalent, or have higher valency.Representative targeting groups include, without limitation, compoundswith affinity to cell surface molecule, cell receptor ligands, hapten,antibodies, monoclonal antibodies, antibody fragments, and antibodymimics with affinity to cell surface molecules. Simply by way ofexample, a variety of ligands can be used to target drugs and genes tocells and to specific cellular receptors, including, without limitation,carbohydrates, glycans, saccharides (including, but not limited to:galactose, galactose derivatives (such as, for example,N-acetyl-galactosamine), mannose, and mannose derivatives), vitamins,folate, biotin, aptamers, and peptides (including, but not limited to:RGD-containing peptides, insulin, EGF, and transferrin). In someembodiments, a targeting group can be linked to an RNAi trigger using alinker, such as a PEG linker or one, two, or three abasic and/or ribitolgroups.

In some embodiments, any of the F12 RNAi triggers listed in Table 3which contain a 3′ or 5′ targeting group or linking group, mayalternatively contain no 3′ or 5′ targeting group or linking group, ormay contain a different 3′ or 5′ targeting group or linking groupincluding, but not limited to, those depicted in Table 4. In someembodiments, an F12 RNAi trigger can include a hydrophobic group such asa cholesterol or a targeting group (e.g. a galactose cluster).

In some embodiments, a targeting group can include or consist of ahydrophobic group. In some embodiments, the hydrophobic group containsat least 20 carbon atoms. Hydrophobic groups can be hydrocarbons (e.g.,containing only carbon and hydrogen atoms). However, substitutions orheteroatoms that maintain hydrophobicity, for example fluorine, arepermitted. Hydrophobic groups useful as targeting groups include,without limitation, alkyl group, alkenyl group, alkynyl group, arylgroup, aralkyl group, aralkenyl group, and aralkynyl group, each ofwhich may be linear, branched, or cyclic, cholesterol, cholesterylderivative, sterol, steroid, and steroid derivative. Examples ofsuitable hydrophobic groups include, without limiation: cholesterol,cholesteryl derivatives, dicholesterol, tocopherol, ditocopherol,didecyl, didodecyl, dioctadecyl, didodecyl, dioctadecyl, isoprenoid, andcholeamide.

In some embodiments, a targeting group can include or consist of one ormore galactose derivatives or galactose clusters. As used herein, theterm galactose derivative includes both galactose and derivatives ofgalactose having affinity for the asialoglycoprotein receptor that isequal to or greater than that of galactose. Glactose derivativesinclude, but are not limited to: galactose, galactosamine,N-formylgalactosamine, N-acetyl-galactosamine,N-propionyl-galactosamine, N-n-butanoyl-galactosamine, andN-iso-butanoylgalactos-amine (see for example: Iobst, S. T. andDrickamer, K. J.B.C. 1996, 271, 6686). Galactose derivatives andgalactose clusters that are useful for in vivo targeting oroligonucleotides and other molecules to the liver are well known in theart (see, for example, Baenziger and Fiete, 1980, Cell, 22, 611-620;Connolly et al., 1982, J. Biol. Chem., 257, 939-945).

As used herein, a galactose cluster comprises a molecule having two tofour terminal galactose derivatives. A terminal galactose derivative cattached to a molecule through its C-1 carbon.

In some embodiments, the galactose cluster is a galactose derivativetrimer, tri-antennary galactose derivative, tri-valent galactosederivative. In some embodiments, the galactose cluster is comprised ofN-acetyl-galactosamine (GalNAc). In some embodiments, the galactosecluster comprises a tri-valent N-acetyl-galactosamine.

As used herein, a galactose derivative trimer contains three galactosederivatives, each linked to a central branch point. The galactosederivatives can be attached to the central branch point through the C-1carbons of the saccharides. In some embodiments, the galactosederivatives are linked to the branch point via linkers or spacers. Insome embodiments, the linker or spacer is a flexible hydrophilic spacer,such as a PEG group (see, for example, U.S. Pat. No. 5,885,968; Biessenet al. J. Med. Chem. 1995 Vol. 39 p. 1538-1546). The branch point can beany small molecule which permits attachment of the three galactosederivatives and further permits attachment of the branch point to theRNAi trigger. An example of branch point group is a di-lysine ordi-glutamate. Attachment of the branch point to the RNAi trigger canoccur through a linker or spacer.

In some embodiments, pharmaceutical compositions for delivering an F12RNAi trigger to a liver cell in vivo are described. Such pharmaceuticalcompositions can include, for example, an F12 RNAi trigger conjugated toa galactose cluster. In some embodiments, the galactose cluster iscomprised of a galactose derivative trimer, which can be, for example,an N-acetyl-galactosamine trimer.

In some embodiments, an F12 RNAi trigger includes a linking groupconjugated to the trigger. The linking group facilitates covalentlinkage of the trigger to a targeting group or delivery polymer. Thelinking group can be linked to the 3′ or the 5′ end of the RNAi triggersense strand or antisense strand. In some embodiments, the linking groupis linked to the RNAi trigger sense strand. In some embodiments, thelinking group is conjugated to the 5′ or 3′ end of an RNAi trigger sensestrand. In some embodiments a linking group is conjugated to the 5′ endof an RNAi trigger sense strand. Examples of linking groups, include orconsist of, but are not limited to: Alk-SMPT-C6, Alk-SS-C6, DBCO-TEG,Me-Alk-SS-C6, and C6-SS-Alk-Me, reactive groups such a primary aminesand alkynes, alkyl groups, abasic ribose, ribitol, and/or PEG groups.

A linker or linking group is a connection between two atoms that linksone chemical group (such as an RNAi agent) or segment of interest toanother chemical group (such as a targeting group or delivery polymer)or segment of interest via one or more covalent bonds. A labile linkagecontains a labile bond. A linkage may optionally include a spacer thatincreases the distance between the two joined atoms. A spacer mayfurther add flexibility and/or length to the linkage. Spacers mayinclude, but are not be limited to, alkyl groups, alkenyl groups,alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, andaralkynyl groups; each of which can contain one or more heteroatoms,heterocycles, amino acids, nucleotides, and saccharides. Spacer groupsare well known in the art and the preceding list is not meant to limitthe scope of the description.

Targeting groups and linking groups include or consist of, but are notlimited to, the compounds represented by the structures shown in Table4. In some of the targeting group and linking group structures shown,the RNAi trigger is shown and denoted by Trigger, RNA, R, or R1 or R2(i.e. Trigger, RNA or R1 or R2 each comprises the RNAi trigger). In someembodiments, the RNAi trigger is linked directly to a targeting group orlinking group. In other embodiments, the RNAi trigger is linked to atargeting group or linking group via a linker. For example, with respectto (Alk-C6-Ser), (Alk-PEG5-Ser), and (Alk-PEG13-Ser), one of R1 and R2comprises the RNAi trigger and the other can be a hydrogen. With respectto linkers (C3), (C12), (Sp9), (Sp18), (Spermine), (C6-SS-C6), one of R1or R2 comprises the RNAi trigger and the other can be a hydrogen,reactive group, targeting group, linking group, alkyl group, orsubstituted alkyl group.

TABLE 4 Structures representing, vpdT, targeting groups and linkinggroups.

vpdT-RNA

(Alk-C6)-Trigger

(Alk-PEG4-C6)-Trigger

(Alk-PEG5-C6)-Trigger or Trigger-(C6-PEG5-Alk)

(Alk-BC9-C6)-Trigger

(Alk-SS-C6)-RNA, (n = 1-10), In some embodiments, n = 4

RNA-(C6-SS-Alk-Me) or ((Me-Alk-SS-C6)-RNA; (n = 1-10), In someembodiments, n = 4.

(Alk-C6-C6)-Trigger or Trigger-(C6-C6-Alk)

(Alk-NHCO-C6)

(Alk-NHCO-SS-C6)

(Alk-C6-Ser)-RNA or RNA-(Ser-C6-Alk), RNA is R1 or R2

(Alk-PEG5-Ser)-RNA, RNA is R1 or R2

(Alk-PEG13-Ser)-RNA, RNA is R1 or R2

(Alk-PEG13-C6)-Trigger

RNA-(C6-SMPT-Alk), n = 1-10, In some embodiments, n = 4

(DBCO-TEG)-Trigger

(BCN)-Trigger

(NH₂-C6)-RNA, n = 1-10, In some embodiments, n = 4.

(NH2-C6)-Trigger or Trigger-(C6-NH2)

(NH2-Ser)-Trigger or Trigger-(Ser-NH2)

(NH2-C7)-Trigger

(Norbornene-C6)-Trigger

(Norbornene-Ser)-Trigger

(TetZ-C6)-Trigger

RNA-(NAG3), x = 1-10, In some embodiments, x = 8.

(NAG3-C6)-Trigger or Trigger-(C6-NAG3)

(C6-C6-NAG3)-Trigger

(C6-C12-NAG3)-Trigger

(C6-PEG4-NAG3)-Trigger

(C11-NAG3)-Trigger

(C11-PEG3-NAG3)-Trigger

RNA-(C11-PEG3-NAG3)

(C11-palm-NAG3)-Trigger

(NAG13)-Trigger

(NAG14)-Trigger

(NAG15)-Trigger

(NAG16)-Trigger

(NAG17)-Trigger

(NAG18)-Trigger

(NAG19)-Trigger

(NAG20)-Trigger

(NAG21)-Trigger

(NAG23)-Trigger

(NAG4)-RNA

((GalNAc-PEG3-ethylene)3 bislysine-PEG3-C7 diol)-Trigger

((GalNAc-PEG3-ethylene)3 bislysine-PEG3-C6)-Trigger

((GalNac-PEG3-methylene)3 bislysine-C6)-Trigger

((GalNac-peg3-methylene)3 bislysine-C7 diol)-Trigger

((GalNac-C6)3 bislysine-C12-C7 diol)-Trigger

(PAZ)-Trigger

(Chol-TEG)-RNA, n = 1-10, In some embodiments, n = 2.

RNA-(TEG-Chol), n = 1-10, In some embodiments, n = 3.

RNA-(C6-SS-C6)(TEG-Chol), n = 1-10, In some embodiments, n = 3.

(Stearyl)-R

(C3)-RNA, RNA is R1 or R2

(C12)-RNA, RNA is R1 or R2

(Sp9)-RNA, RNA is R1 or R2

(Sp18)-RNA, RNA is R1 or R2

(Spermine)-RNA, RNA is R1 or R2

(C6-SS-C6)-RNA, RNA is R1 or R2

(Cy5-C6)-Trigger

In some embodiments, a delivery vehicle may be used to delivery an RNAitrigger to a cell or tissue. A delivery vehicle is a compound thatimproves delivery of the RNAi trigger to a cell or tissue. A deliveryvehicle can include, or consist of, but is not limited to: a polymer,such as an amphipathic polymer, a membrane active polymer, a peptide, amelittin peptide, a melittin-like peptide, a lipid, or a reversiblymodified polymer or peptide.

As used herein, the term “sequence” or “nucleotide sequence” refers to asuccession or order of nucleobases or nucleotides, described with asuccession of letters using the standard nucleotide nomenclature and thekey for modified nucleotides described herein.

As used herein, and unless otherwise indicated, the term“complementary,” when used to describe a first nucleotide sequence(e.g., RNAi trigger sense strand or F12 mRNA) in relation to a secondnucleotide sequence (e.g. RNAi trigger antisense strand), refers to theability of an oligonucleotide or polynucleotide comprising the firstnucleotide sequence to hybridize (form base pair hydrogen bonds) andform a duplex or double helical structure under certain conditions withan oligonucleotide or polynucleotide comprising the second nucleotidesequence. Complementary sequences include Watson-Crick base pairs ornon-Watson-Crick base pairs and include natural or modified nucleotidesor nucleotide mimics as long as the above requirements with respect totheir ability to hybridize are fulfilled. “Perfectly” or fullycomplementary” means that all (100%) of the bases in a contiguoussequence of a first polynucleotide will hybridize with the same numberof bases in a contiguous sequence of a second polynucleotide. Thecontiguous sequence may comprise all or a part of a first or secondnucleotide sequence. As used herein, “partial complementary” means thatin a hybridized pair of nucleobase sequences, at least 70% of the basesin a contiguous sequence of a first polynucleotide will hybridize withthe same number of bases in a contiguous sequence of a secondpolynucleotide. As used herein, “substantial complementary” means thatin a hybridized pair of nucleobase sequences, at least 85% of the basesin a contiguous sequence of a first polynucleotide will hybridize withthe same number of bases in a contiguous sequence of a secondpolynucleotide. The terms “complementary”, “fully complementary” and“substantially complementary” as used herein may be used with respect tothe base matching between the sense strand and the antisense strand ofan RNAi trigger, or between the antisense strand of an RNAi trigger anda sequence of an F12 mRNA.

Sequence identity or complementarity is independent of modification. Forthe purposes of determining identity or complementarity, for example, aand Af are complementary to U (or T) and identical to A.

In some embodiments, an F12 RNAi trigger can be used to treat a subjecthaving a disease or disorder that would benefit from reducing orinhibiting of expression of F12. In some embodiments, an F12 RNAitrigger can be used to formulate a composition for treating a disease ordisorder in a subject that would benefit from reducing or inhibiting ofexpression of F12. The example, a subject can be administered atherapeutically effective amount of any one or more of the F12 RNAitriggers or compositions described herein. The subject also can bereferred to as a patient, and can be a human or animal patient. Thedescribed F12 RNAi triggers can be used to provide a method fortherapeutic treatment of diseases. Such methods typically includeadministration of an F12 RNAi trigger described herein to a subject.

In some embodiments, an F12 RNAi trigger can be used to inhibitingexpression of F12 in a cell, group of cells, or a tissue, e.g., in asubject. In some embodiments, an F12 RNAi trigger can be used toformulate a composition for inhibiting expression of F12 in a cell,group of cells, or a tissue, e.g., in a subject. In some embodiments, atherapeutically effective amount of one type (or several differenttypes) of F12 RNAi triggers as described herein is administered to asubject, thereby inhibiting expression of F12 in the subject (e.g., anamount effective to inhibit expression of F12 in the subject).

As used herein, the terms “silence,” “reduce,” “inhibit,”“down-regulate,” or “knockdown gene expression,” when referring to anF12 gene, mean that the expression of the gene, as measured by the levelof RNA transcribed from the gene or the level of polypeptide, protein,or protein subunit translated from the mRNA in a cell, group of cells,or tissue, in which the F12 gene is transcribed, is reduced when thecell, group of cells, or tissue, is treated with the described F12 RNAitriggers as compared to a second cell, group of cells, or tissue thathas or have not been so treated or compared to the same cell, group ofcells, or tissue, prior to administration of the F12 RNAi trigger.

In some embodiments, the F12 RNAi triggers described herein are used totreat a subject having a disease or disorder that would benefit fromreduction or inhibition in F12 expression. Treatment of a subject thatwould benefit from a reduction and/or inhibition of F12 gene expressionincludes therapeutic and/or prophylactic treatment. Representativediseases are those associated with angioedema, including but not limitedto: hereditary angioedema (HAE), acquired angioedema (AAE), includingbut not limited to ACE inhibitor associated angioedema, allergicangioedema, nonhistaminergic angioedema (INAE), idiopathic angioedema,thrombosis, venous thromboembolism (VTE), thrombotic occlusive disease,including but not limited to peri-operative venous occlusive diseaseprophylaxis, treatment and prevention of venous occlusive disease suchas deep venous thrombosis or pulmonary embolism, and treatment orprevention of arterial thromboembolic disease.

In some embodiments, pharmaceutical compositions comprising at least oneof the described F12 RNAi triggers are contemplated. Thesepharmaceutical compositions are useful in the inhibition of theexpression of the F12 gene in a cell, a tissue, or an organism. In someembodiments, the described pharmaceutical compositions are used to treata subject having a disease or disorder that would benefit from reductionor inhibition in F12 expression. In some embodiments, the describedpharmaceutical compositions are used to treat a subject at risk ofdeveloping a disease or disorder that would benefit from reduction orinhibition in F12 expression. Diseases and/or disorder that wouldbenefit from reduction or inhibition in F12 expression may be selectedfrom the list comprising: angioedema, HAE, AAE, allergic angioedema,INAE, idiopathic angioedema, thrombosis, VTE, thrombotic occlusivedisease, venous occlusive disease, and arterial thromboembolic disease.In some embodiments, the subject is a mammal, including, but not limitedto, a human patient. In some embodiments, the method comprisesadministering a composition comprising an F12 RNAi trigger moleculedescribed herein to a mammal to be treated. The pharmaceuticalcompositions described above may also comprise a one or morepharmaceutically acceptable excipients (including vehicles, carriers,diluents, and/or delivery polymers).

As used herein, a “pharmaceutical composition” comprises apharmacologically effective amount of at least one RNAi trigger and oneor more a pharmaceutically acceptable excipients. Pharmaceuticallyacceptable excipients (excipients) are substances other than the ActivePharmaceutical ingredient (API, therapeutic product, e.g., RNAi trigger)that have been appropriately evaluated for safety and are intentionallyincluded in the drug delivery system. Excipients do not exert or are notintended to exert a therapeutic effect at the intended dosage.Excipients may act to a) aid in processing of the drug delivery systemduring manufacture, b) protect, support or enhance stability,bioavailability or patient acceptability of the API, c) assist inproduct identification, and/or d) enhance any other attribute of theoverall safety, effectiveness, of delivery of the API during storage oruse. A pharmaceutically acceptable excipient may or may not be an inertsubstance.

Excipients include, but are not limited to: absorption enhancers,anti-adherents, anti-foaming agents, anti-oxidants, binders, binders,buffering agents, carriers, coating agents, colors, delivery enhancers,dextran, dextrose, diluents, disintegrants, emulsifiers, extenders,fillers, flavors, glidants, humectants, lubricants, oils, polymers,preservatives, saline, salts, solvents, sugars, suspending agents,sustained release matrices, sweeteners, thickening agents, tonicityagents, vehicles, water-repelling agents, and wetting agents.

The pharmaceutical compositions can contain other additional componentscommonly found in pharmaceutical compositions. Such additionalcomponents can include, but are not limited to: anti-pruritics,astringents, local anesthetics, or anti-inflammatory agents (e.g.,antihistamine, diphenhydramine, etc.). It is also envisaged that cells,tissues or isolated organs that express or comprise the herein definedRNAi triggers may be used as “pharmaceutical compositions”. As usedherein, “pharmacologically effective amount,” “therapeutically effectiveamount,” or simply “effective amount” refers to that amount of an RNAitrigger to produce the intended pharmacological, therapeutic orpreventive result.

In other embodiments, the F12 RNAi triggers are useful for treating,preventing, or managing clinical presentations associated withangioedema, hereditary angioedema (HAE), acquired angioedema (AAE),allergic angioedema, nonhistaminergic angioedema (INAE), idiopathicangioedema, thrombosis, venous thromboembolism (VTE), thromboticocclusive disease, venous occlusive disease, and arterial thromboembolicdisease. Said methods comprise administering to a subject in need ofsuch treatment, prevention or management a therapeutically orprophylactically effective amount of one or more of the F12 RNAitriggers described herein. In some embodiments, the subject is a mammal,including, but not limited to, a human patient. In some embodiments, themethod comprises administering a composition comprising an F12 RNAitrigger molecule described herein to a mammal to be treated.

In some embodiments, the described F12 RNAi triggers and methods ofusing such F12 RNAi triggers are used to treat or prevent at least onesymptom in a subject having a disease or disorder that would benefitfrom reduction or inhibition in F12 expression. The subject isadministered a therapeutically effective amount of any one or more ofthe described RNAi triggers thereby treating the symptom. The subject isadministered a prophylactically effective amount of any one or more ofthe described RNAi triggers thereby preventing the at least one symptom.

In some embodiments, the gene expression level and/or mRNA level of F12in a subject to whom a described F12 RNAi trigger is administered isreduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to thesubject prior to being administered the F12 RNAi trigger or to a subjectnot receiving the F12 RNAi trigger. The gene expression level and/ormRNA level in the subject may be reduced in a cell, group of cells,and/or tissue of the subject. In some embodiments, the protein level ofF12 in a subject to whom a described F12 RNAi trigger has beenadministered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%relative to the subject prior to being administered the F12 RNAi triggeror to a subject not receiving the F12 RNAi trigger. The protein level inthe subject may be reduced in a cell, group of cells, tissue, blood,and/or other fluid of the subject. A reduction in gene expression, mRNA,or protein levels can be assessed by any methods known in the art.Reduction or decrease in F12 mRNA level and/or protein level arecollectively referred to herein as a reduction or decrease in F12 orinhibiting or reducing the expression of F12.

The described F12 RNAi triggers can be combined a second therapeutic ortreatment including, but not limited to: a second RNAi trigger or otherRNAi agent, a small molecule drug, an antibody, an antibody fragment,and/or a vaccine.

The described RNAi triggers and pharmaceutical compositions comprisingF12 RNAi triggers disclosed herein may be packaged or included in a kit,container, pack, or dispenser. The F12 RNAi triggers may be packaged inpre-filled syringes or vials.

“Introducing into a cell”, when referring to an RNAi trigger, meansfunctionally delivering the RNAi trigger into a cell. By functionaldelivery, it is meant that the RNAi trigger is delivered to the cell andhas the expected biological activity, (e.g., sequence-specificinhibition of gene expression).

The route of administration is the path by which an RNAi trigger isbrought into contact with the body. In general, methods of administeringdrugs and nucleic acids for treatment of a subject are well known in theart and can be applied to administration of the compositions describedherein. The compounds described herein can be administered via anysuitable route in a preparation appropriately tailored to the particularroute. Thus, the compounds described herein can be administered byinjection, for example, intravenously, intramuscularly,intracutaneously, subcutaneously, or intraperitoneally.

In some embodiments, the F12 RNAi trigger molecules or compositionsdescribed herein can be delivered to a cell, group of cells, tissue, orsubject using oligonucleotide delivery technologies known in the art. Ingeneral, any suitable method recognized in the art for delivering anucleic acid molecule (in vitro or in vivo) can be adapted for use withan F12 RNAi trigger described herein. For example, delivery can be bylocal administration, (e.g., direct injection, implantation, or topicaladministering), systemic administration, or subcutaneous, intravenous,oral, intraperitoneal, or parenteral routes, including intracranial(e.g., intraventricular, intraparenchymal and intrathecal),intramuscular, transdermal, airway (aerosol), nasal, rectal, or topical(including buccal and sublingual) administration, In certainembodiments, the compositions are administered by subcutaneous orintravenous infusion or injection.

In some embodiments, the RNAi triggers can be combined with lipids,nanoparticles, polymers, liposomes, micelles, DPCs or other deliverysystems available in the art. The RNAi triggers can also be chemicallyconjugated to targeting groups, lipids (including, but not limited tocholesterol and cholesteryl derivatives), nanoparticles, polymers,liposomes, micelles, DPCs (se e.g., WO 2000/053722, WO 2008/0022309, WO2011/104169, and WO 2012/083185, each of which is incorporated herein byreference), or other delivery systems available in the art.

In some embodiments, an RNAi trigger can be conjugated to a deliverypolymer. In some embodiments, the delivery polymer is a reversiblymasked/modified amphipathic membrane active polyamine.

In some embodiments, an F12 RNAi trigger-targeting group conjugate canbe co-administered with a melittin-like peptide (MLP) delivery peptide(e.g., an active excipient). By co-administered it is meant that the F12RNAi trigger and the delivery peptide are administered to the subjectsuch that both are present in the subject at the same time. The F12 RNAitrigger-targeting group conjugate and the delivery peptide may beadministered simultaneously or they may be delivered sequentially. Forsimultaneous administration, the F12 RNAi trigger-targeting groupconjugate and the delivery peptide can be mixed prior to administration.For sequential administration, either the F12 RNAi trigger-group moietyconjugate or the delivery peptide can be administered first.

In some embodiments, pharmaceutical compositions for delivering an F12RNAi trigger to a liver cell in vivo are described. Such pharmaceuticalcompositions can include or consist of: a) an F12 RNAi triggerconjugated to a hydrophobic group containing at least 20 carbon atoms(RNAi trigger-conjugate), such as a cholesterol and b) an MLP deliverypolymer. The MLP delivery polymer and the RNAi trigger-conjugate can besynthesized separately and may be supplied in separate containers or asingle container. In some embodiments, the F12 RNAi trigger is notconjugated to the delivery peptide.

Melittin-like peptide (MLP), as used herein, is a small amphipathicmembrane active peptide, comprising about 23 to about 32 amino acidsderived from the naturally occurring bee venom peptide, melittin, asdescribed in WO 2012/083185. The naturally occurring melittin contains26 amino acids and is predominantly hydrophobic on the amino terminalend and predominantly hydrophilic (cationic) on the carboxy terminalend. In some embodiments, the MLP described herein is isolated from abiological source. In other embodiments, the MLP is synthetic. A MLPsynthetic polymer can be formulated or manufactured by a chemicalprocess.

As used herein, MLP encompasses the naturally occurring bee venompeptides of the melittin family that can be found in, for example, venomof the species: Apis florea, Apis mellifera, Apis cerana, Apis dorsata,Vespula maculifrons, Vespa magnifica, Vespa velutina, Polistes sp.HQL-2001, and Polistes hebraeus. As used herein, MLP also encompassessynthetic peptides having amino acid sequence identical to or similar tonaturally occurring melittin peptides. Examples of MLP amino acidsequences include those provided in Table 5. In some embodiments, MLPcomprises:Leu-Ile-Gly-Ala-Ile-Leu-Lys-Val-Leu-Ale-Thr-Gly-Leu-Pro-Thr-Leu-Ile-Ser-Trp-Ile-Lys-Asn-Lys-Arg-Lys-Gln(SEQ ID 2234).

TABLE 5 MLP peptide sequences. SEQ ID NO. Melittin Sequence Name 2228GIGAILKVLATGLPTLISWIKNKRKQ Apis florea 2229 AIGAILKVLATGLPTLISWIKNKRKQG1A 2230 CIGAILKVLATGLPTLISWIKNKRKQ G1C 2231 FIGAILKVLATGLPTLISWIKNKRKQG1F 2232 HIGAILKVLATGLPTLISWIKNKRKQ G1H 2233 IIGAILKVLATGLPTLISWIKNKRKQG1I 2234 LIGAILKVLATGLPTLISWIKNKRKQ G1L 2235NleIGAILKVLATGLPTLISWIKNKRKQ G1Nle 2236 VIGAILKVLATGLPTLISWIKNKRKQ G1V2237 WIGAILKVLATGLPTLISWIKNKRKQ G1W 2238 YIGAILKVLATGLPTLISWIKNKRKQ G1Y2239 GIGAILKVLACGLPTLISWIKNKRKQ T11C dMel 2240GIGAILKVLATLLPTLISWIKNKRKQ G12L 2241 GIGAILKVLATWLPTLISWIKNKRKQ G12W2242 GIGAILKVLATGLPTLISWIKTKRKQ N22T 2243 YIGAILNVLATGLPTLISWIKNKRKQG1Y, K7N 2244 YIGAILAVLATGLPTLISWIKNKRKQ G1Y, K7A 2245LIGAILSVLATGLPTLISWIKNKRKQ G1L, K7S 2246 LIGAILRVLATGLPTLISWIKNKRKQ G1L,K7R 2247 LIGAILHVLATGLPTLISWIKNKRKQ G1L, K7H 2248LIGAILKVLACGLPTLISWIKNKRKQ G1L, T11C 2249 LIGAILKVLATLLPTLISWIKNKRKQG1L, G12L 2250 YIGAILKVLATGLLTLISWIKNKRKQ G1Y, P14L 2251LIGAILKVLATGLPCLISWIKNKRKQ G1L, T15C 2252 LIGAILKVLATGLPTLICWIKNKRKQG1L, S18C 2253 YIGAILKVLATGLPTLISAIKNKRKQ G1Y, W19A 2254GIGAILKVLACGLPTLISWLKNKRKQ T11C, I20L 2255 YIGAILKVLATGLPTLISWIANKRKQG1Y, K21A 2256 YIGAILKVLATGLPTLISWIKNARKQ G1Y, K23A 2257LIGAILKVLATGLPTLISWIKNKAKQ G1L, R24A 2258 YIGAILKVLATGLPTLISWIKNKRAQG1Y, K25A 2259 YIGAILKVLATGLPTLISWIKNKRKC G1Y, Q26C 2260LLGAILKVLACGLPTLISWIKNKRKQ G1L, I2L, T11C 2261LIGALLKVLACGLPTLISWIKNKRKQ G1L, I5L, T11C 2262YIGAILAVLATGLPTLISWIANKRKQ G1Y, K7A, K21A 2263YIGAILAVLATGLPTLISWIKNARKQ G1Y, K7A, K23A 2264LIGAILKVLACGLPTLLSWIKNKRKQ G1L, T11C, I17L 2265LIGAILKVLACG1PTLICWIKNKRKQ G1L, T11C, S18C 2266GIGAILKVLACGLPGLIGWIKNKRKQ T11G, T15G, S18G 2267GIGAILKVLACGLPALIAWIKNKRKQ T11A, T15A, S18A 2268YIGAILAVLATGLPTLISWIANARKQ G1Y, K7A, K21A, K23A 2269YIAAILKVLAAALATLISWIKNKRKQ G1Y, G3A, T11A, G12A, P14A 2270LLGALLKVLATGLPTLLSWLKNKRKQ G1L, I2L, 15L, I17L, I20L 2271LNleGANleLKVLATGLPTLNleSWNleKNKRKQ G1L, I2Nle, I5Nle, I17Nle, I20Nle2272 LVGAVLKVLATGLPTLVSWVKNKRKQ G1L, I2V, I5V, I17V, 120V 2273GLGALLKVLACGLPTLLSWLKNKRKQ I2L, I5L, T11C, I17L, I20L 2274GNleGANleLKVLACGLPTLNleSWNleKNKRKQ I2Nle, I5Nle, T11C, I17Nle, I20Nle2275 CEDDLLLGAILKVLATGLPTLISWIKNKRKQ CEDDL-Mel G1L, I2L 2276CLVVLIVVAILKVLATGLPTLISWIKNKRKQ CLVVL-Mel G1I, I2V, G3V 2277GIGAVLKVLTTGLPALISWIKRKRQQ Apis mellifera 2278CLIGAILKVLATGLPTLISWIKNKRKQ C-Mel G1L 2279 CNleIGAILKVLATGLPTLISWIKNKRKQC-Mel G1Nle 2280 GLIGAILKVLATGLPTLISWIKNKRKQ G-Mel G1L 2281LLIGAILKVLATGLPTLISWIKNKRKQ L-Mel G1L 2282 KLKLIGAILKVLATGLPTLISWIKNKRKQKLK-Mel G1L 2283 KLKYIGAILKVLATGLPTLISWIKNKRKQ KLK-Mel G1Y 2284CKLKLIGAILKVLATGLPTLISWIKNKRKQ CKLK-Mel G1L 2285CKLKNleIGAILKVLATGLPTLISWIKNKRKQ CKLK-Mel G1Nle 2286GKLKLIGAILKVLATGLPTLISWIKNKRKQ GKLK-Mel G1L 2287CPANLIGAILKVLATGLPTLISWIKNKRKQ CPAN-dMel G1L 2288DEPLRAIGAILKVLATGLPTLISWIKNKRKQ DEPLR-Mel G1A 2289GIGAILKVLATGLPTLISWIKNKRKQC Mel-Cys 2290 LIGAILKVLATGLPTLISWIKNKRKQC G1LMel-Cys 2291 NleIGAILKVLATGLPTLISWIKNKRKQC G1Nle Mel-C 2292LIGAILKVLATGLPTLISWIKNKRKQKLKC G1L Mel-KLKC 2293YIGAILKVLATGLPTLISWIKNKRKQPLGIAGQC G1Y Mel-PLGIAGQC 2294LIGAILKVLATGLPTLISWIKNKRKQKKKKK G1L Mel-KKKKK 2295YIGAILKVLATGLPTLISWIKNKRKQGFKGC G1Y Mel-GFKGC 2296CFKLIGAILKVLATGLPTLISWIKNKRKQC CFK-G1L Mel-C 2297FGAILKVLATGLPTLISWIKNKRKQ G1F, I2Δ 2298 LIGAILKVLATGLPTLISWIKNK G1L Mel(1-23) 2299 LIGAVLKVLTTGLPALISWIK G1L, L5V, A10T, T15A Mel (1-23) 2300LIGAVLKVLTTGLPALISWIKGE G1L, L5V, A10T, T15A, N22G, K23E Mel (1-23) 2301QKRKNKIWSILTPLGTALVKLIAGIL G1L retroMel 2302KLKQKRKNKIWSILTPLGTALVKLIAGIL G1L retroMel-KLK 2303GIGAVLKVLTTGLPALISWISRKKRQQ I5V, A10T, T15A, N22R, R24K, K25R Mel-Q 2304GIGARLKVLTTGLPRISWIKRKRQQ I5R, A10T, T15R, L16Δ, N22R, K25Q 2305GIGAILKVLSTGLPALISWIKRKRQE A10S, T15A, N22R, K25Q, Q26E 2306GIGAVLKVLTTGLPALIGWIKRKRQQ I5V, A10T, T15A, S18G, N22R, K25Q 2307GIGAVLKVLATGLPALISWIKRKRQQ I5V, T15A, N22R, K25Q 2308GIGAVLKVLSTGLPALISWIKRKRQQ I5V, A10S, T15A, N22R, K25Q 2309GIGAILRVLATGLPTLISWIKNKRKQ K7R 2310 GIGAILKVLATGLPTLISWIKRKRKQ N22R 2311GIGAILKVLATGLPTLISWIKKKKQQ N22K, R24K, K25Q 2312GIGAILKVLATGLPTLISWIKNKRKQGSKKKK Mel-GSKKKK 2313KKGIGAILKVLATGLPTLISWIKNKRKQ KK-Mel 2314 GIGAILEVLATGLPTLISWIKNKRKQ K7EMel 2315 GIGAVLKVLTTGLPALISWIKRKR I5V, T15A, N22R, 25-26Δ 2316GIGAVLKVLTTGLPALISWIKR I5V, T15A, N22R, 23-26Δ 2317CIGAVLKVLTTGLPALISWIKRKRQQ G1C, I5L, T15A, N22R 2318QQRKRKIWSILAPLGTTLVKLVAGIG I5V, A10T, T15A, N22R retroMel 2319QQRKRKIWSILAPLGTTLVKLVAGIC G1C, I5V, A10T, T15A, N22R retroMel 2320QQKKKKIWSILAPLGTTLVKLVAGIC G1C, I5V, A10T, T15A, N22R, R24K retroMel2321 QKRKNKIWSILTPLGTALVKLIAGIG Q25K reverse Mel 2322QQRKRKIWSILAALGTTLVKLVAGIC G1C, I5V, A10T, P14A, T15A, N22R retroMeldMel = Melittin peptide having D-form amino acids Nle = norluecine

Membrane activity of the MLPs can be reversibly masked to yield MLPdelivery polymers. Masking can be accomplished through reversibleattachment of masking agents to primary amines of the MLP.

An MLP delivery polymer can include an MLP reversibly modified byreaction of primary amines on the peptide with asialoglycoproteinreceptor (ASGPr) ligand-containing masking agents, wherein thereversible modification can be physiologically labile, as described inWO 2012/083185. In some embodiments, the masking agent comprises aneutral hydrophilic disubstituted alkylmaleic anhydride:

wherein R1 comprises an uncharged asialoglycoprotein receptor ligand. Insome embodiments, the alkyl group is a methyl or ethyl group. An exampleof a substituted alkylmaleic anhydride is a 2-propionic-3-alkylmaleicanhydride derivative. A neutral hydrophilic 2-propionic-3-alkylmaleicanhydride derivative can be formed by attachment of a neutralhydrophilic group to a 2-propionic-3-alkylmaleic anhydride through the2-propionic-3-alkylmaleic anhydride γ-carboxyl group:

wherein R1 includes a neutral ASGPr ligand and n=0 or 1. In someembodiments, the ASGPr ligand can be linked to the anhydride via a shortPEG linker.

The ASGPr ligand provides targeting function through affinity for ASGPr.ASGPr ligands contain saccharides having affinity for the ASGPr,including but not limited to: galactose, N-acetyl-galactosamine andgalactose derivatives. Galactose derivatives having affinity for theASGPr are well known in the art.

In some embodiments, a composition is described that includes:

N−T and MLP−(L−M)_(x),

wherein N is an F12 RNAi trigger, T comprises a hydrophobic group having20 or more carbon atoms, such as cholesterol, MLP is a melittin-likepeptide, and M contains an ASGPr ligand covalently linked to MLP via aphysiologically labile reversible maleamate linkage L. x is an integergreater than 1. More specifically, the value of x is greater than 80%,greater than 90%, or greater than 95% of the number of primary amines ona population MLP. As used herein, MLP−(L−M)_(x) can be referred to as anMLP delivery polymer (e.g., an excipient). In some embodiments, an F12RNAi trigger-cholesterol conjugate and an MLP delivery polymer can besupplied in the same container. In other embodiments, an F12 RNAitrigger-cholesterol conjugate and an MLP delivery polymer can besupplied in separate containers. An F12 RNAi trigger-cholesterolconjugate and an MLP delivery polymer may be combined prior toadministration, co-administered, or administered sequentially.

Cells, tissues, and non-human organisms that include at least one of theRNAi triggers described herein is contemplated. The cell, tissue, ornon-human organism is made by delivering the RNAi trigger to the cell,tissue, or non-human organism by any means available in the art. In someembodiments, the cell is a mammalian cell, including, but no limited to,a human cell. The cell, tissue, or non-human organisms are useful forresearch or as research tools (e.g., drug testing or diagnoses).

The above provided embodiments and items are now illustrated with thefollowing, non-limiting examples.

EXAMPLES Example 1. RNAi Trigger Synthesis

A) Synthesis. RNAi trigger molecules were synthesized according tophosphoramidite technology on solid phase used in oligonucleotidesynthesis. Depending on the scale either a MerMade96E (Bioautomation) ora MerMade12 (Bioautomation) was used. Syntheses were performed on asolid support made of controlled pore glass (CPG, 500 Å or 600 Å,obtained from Prime Synthesis, Aston, Pa., USA). All DNA, 2′-modifiedRNA, and UNA phosphoramidites were purchased from Thermo FisherScientific (Milwaukee, Wis., USA). Specifically, the following2′-O-Methyl phosphoramidites were used:(5′-O-dimethoxytrityl-N⁶-(benzoyl)-2′-O-methyl-adenosine-3′-O-(2-cyanoethyl-N,N-diisopropy-lamino)phosphoramidite,5′-O-dimethoxy-trityl-N⁴-(acetyl)-2′-O-methyl-cytidine-3′-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite,(5′-O-dimethoxytrityl-N²-(isobutyryl)-2′-O-methyl-guanosine-3′-O-(2-cyano-ethyl-N,N-diisopropylamino)phosphoramidite,and5′-O-dimethoxy-trityl-2′-O-methyl-uridine-3′-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite.The 2′-Deoxy-2′-fluoro-phosphor-amidites carried the same protectinggroups as the 2′-O-methyl RNA amidites. The following UNAphosphoramidites were used:5′-(4,4′-Dimethoxytrityl)-N-benzoyl-2′,3′-seco-adenosine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite,5′-(4,4′-Dimethoxytrityl)-N-acetyl-2′,3′-seco-cytosine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite,5′-(4,4′-Dimethoxytrityl)-N-isobutyryl-2′,3′-seco-guanosine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and5′-(4,4′-Dimethoxytrityl)-2′,3′-seco-uridine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. Allamidites were dissolved in anhydrous acetonitrile (50 mM) and molecularsieves (3 Å) were added. In order to introduce the TEG-Cholesterol atthe 5′-end of the oligomers, the1-Dimethoxytrityloxy-3-O-(N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-2-O-(2-cyanoethyl)-(N,N,-diisopropyl)-phosphoramiditefrom Glen Research (Sterling, Va., USA) was employed. The5′-modifications were introduced without any modification of thesynthesis cycle. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile)was used as activator solution. Coupling times were 10 min (RNA), 180sec (Cholesterol), 90 sec (2′OMe and UNA), and 60 sec (2′F and DNA). Inorder to introduce phosphorothioate linkages, a 100 mM solution of3-phenyl 1,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc.,Leominster, Mass., USA) in anhydrous Acetonitrile was employed. SeeTables 1-3 for specific sequences.

B. Cleavage and deprotection of support bound oligomer. Afterfinalization of the solid phase synthesis, the dried solid support wastreated with a 1:1 volume solution of 40 wt. % methylamine in water and28% ammonium hydroxide solution (Aldrich) for two hours at 30° C. Thesolution was evaporated and the solid residue was reconstituted in water(see below).

C. Purification. Crude Cholesterol containing oligomers were purified byreverse phase HPLC using a Waters XBridge BEH300 C4 5u Prep column and aShimadzu LC-8 system. Buffer A was 100 mM TEAA, pH 7.5 and contained 5%Acetonitrile and buffer B was 100 mM TEAA and contained 95%Acetonitrile. UV traces at 260 nm were recorded. Appropriate fractionswere then run on size exclusion HPLC using a GE Healthcare XK 16/40column packed with Sephadex G-25 medium with a running buffer of 100 mMammonium bicarbonate, pH 6.7 and 20% Acetonitrile. Other crude oligomerswere purified by anionic exchange I-IPLC using a TKSgel SuperQ-5PW 13ucolumn and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH9.0 and contained 20% Acetonitrile and buffer B was the same as buffer Awith the addition of 1.5 M sodium chloride. UV traces at 260 nm wererecorded. Appropriate fractions were pooled then run on size exclusionHPLC as described for cholesterol containing oligomers.

D. Annealing. Complementary strands were mixed by combining equimolarsolutions (sense and antisense) in 0.2x PBS (Phosphate-Buffered Saline,1×, Corning, Cellgro) to form the RNAi triggers. This solution wasplaced into a thermomixer at 70° C., heated to 95° C., held at 95° C.for 5 min, and cooled to room temperature slowly. Some RNAi triggerswere lyophilized and stored at −15 to −25° C. Duplex concentration wasdetermined by measuring the solution absorbance on a UV-Vis spectrometerin 0.2x PBS. The solution absorbance at 260 nm was then multiplied by aconversion factor and the dilution factor to determine the duplexconcentration. Unless otherwise stated, all conversion factor was 0.037mg/(mL·cm). For some experiments, a conversion factor was calculatedfrom an experimentally determined extinction coefficient.

Example 2. Melittin-Like-Peptide (MLP) Delivery Polymer

A) Melittin-Like-Peptide (MLP) synthesis. All MLPs were made usingpeptide synthesis techniques standard in the art. Independently of L orD form, the MLP sequence can be reversed (retro).

B) CDM-NAG (N-acetyl galactosamine) synthesis. To a solution of CDM (300mg, 0.16 mmol) in 50 mL methylene chloride was added oxalyl chloride (2g, 10 wt. eq.) and dimethylformamide (5 μl). The reaction was allowed toproceed overnight, after which the excess oxalyl chloride and methylenechloride were removed by rotary evaporation to yield the CDM acidchloride. The acid chloride was dissolved in 1 mL of methylene chloride.To this solution was added 1.1 molar equivalents(aminoethoxy)ethoxy-2-(acetylamino)-2-deoxy-(3-D-galactopyranoside (i.e.amino bisethoxyl-ethyl NAG) and pyridine (200 μl, 1.5 eq) in 10 mL ofmethylene chloride. The solution was then stirred 1.5 h. The solvent wasthen removed and the resulting solid was dissolved into 5 mL of waterand purified using reverse-phase HPLC using a 0.1% TFAwater/acetonitrile gradient.

R1 comprises a neutral ASGPr ligand. In some embodiments, the MaskingAgent is uncharged.

n is an integer from 1 to 10. As shown above, a PEG spacer may bepositioned between the anhydride group and the ASGPr ligand. In someembodiments, a PEG spacer contains 1-10 ethylene units. Alternatively analkyl spacer may be used between the anhydride and theN-acetyl-galactosamine (NAG).

n is a integer from 0 to 6.

Other spacers or linkers may be used between the anhydride and theN-acetyl-galactosamine.

In some embodiments, the spacer or linker is, a hydrophilic, and neutralor uncharged.

C) Formation of the MLP delivery polymer (i.e. masking). The MLP wasreacted with CDM-NAG masking agent to yield the MLP delivery polymer.The MLP component was first dissolved to a final concentration of 8.5mg/mL in aqueous HEPES (sodium salt, GMP grade, ˜430 mg/mL). The MLPsolution was then cooled to 4° C., and checked for appearance (clear topale yellow solution free of visible particulate) and for concentrationby UV spectrophotometry. CDM-NAG was dissolved in water at 4° C. at afinal concentration of ˜75 mg/mL. The solution was checked forappearance (clear to pale yellow solution free of visible particulate)and for concentration by UV spectrophotometry. MLP in solution was mixedwith CDM-NAG in solution at a 5:1 (w/w) ratio of CDM-NAG to MLP. Theaddition rate of CDM-NAG solution was approximately 0.3 L per minute,while stirring. After all CDM-NAG solution had been added to the MLPsolution, the mixture was stirred for 30 min. To stabilize the MLPdelivery polymer, the pH was increased to 9.0±0.2 by addition of 1 Maqueous sodium hydroxide. Reaction of disubstituted maleic anhydridemasking agent with the peptide yielded a compound having the structurerepresented by:

wherein R is MLP and R1 comprises an ASGPr ligand (e.g. NAG).

Colorimetric trinitrobenzene sulfonic acid (TNBS) assay of remainingfree amines was used to determine that MLP was sufficiently masked byCDM-NAG, less than 10% of the total number of MLP amines remainedunmodified.

MLP delivery polymer was purified by diafiltration against 10 mM, pH 9.2carbonate buffer to remove excess CDM-NAG. The diafiltration processexchanged ˜10 volumes of carbonate buffer per volume of masked MLPreaction solution and held at 2-8° C.

Component Quantity (nominal) MLP  30 g/L CDM-NAG^(a)  25 g/L Sodiumcarbonate 0.3 g/L Sodium bicarbonate 0.6 g/L Water 1000 g/L  ^(a)assumes five (5) CDM-NAG moieties per MLP

The MLP delivery polymer was further formulated with Dextran to 10% w/vand stored at 2 to 8° C. 228 mg MLP delivery polymer, 500 mg 1 kDadextran, 1.59 mg Na₂CO₃, 2.94 mg NaHCO₃. For some experiments, thissolution was lyophilized prior to use.

D) Injection solution. The injection solution was formed by mixing RNAitrigger with the MLP delivery polymer. The lyophilized MLP deliverypolymer was dissolved in water and mixed with the RNAi trigger. Thatsolution was then diluted to the correct injection concentration withnormal saline.

Example 3. In Vitro Screening of F12 RNAi Triggers

A) Human cell background. Candidate sequences identified as human,non-human primate and mouse cross-reactive by in silico analysis werescreened as chemically modified canonical siRNAs in vitro. Thirty-two ofthe in silico identified potential F12 RNAi triggers were synthesized ascanonical siRNAs and screened for efficacy in vitro. For screeningpurposes, the human F12 cDNA sequence (accession #NM_000505) wassynthesized and cloned (DNA 2.0, Menlo Park, Calif.) into acommercially-available reporter-based screening plasmid, psiCHECK2(Promega, Madison, Wis.) which generated a Renilla luciferase/F12 fusionmRNA.

For siRNA efficacy in the human background, Hep3B cells, a humanhepatocellular carcinoma line, were plated at ˜10,000 cells per well in96-well format. Each of the 32 F12 siRNAs was co-transfected at twoconcentrations, 1 nM and 0.1 nM, with 25 ng F12-psiCHECK2 plasmid DNAper well and 0.2 μL LipoFectamine 2000 per well. Gene knockdown wasdetermined by measuring Renilla luciferase levels normalized to thelevels of constitutively-expressed firefly luciferase, also present onthe psiCHECK2 plasmid, using the Dual Luciferase Reporter Assay(Promega, Madison, Wis.).

TABLE 6 Efficacy screen results of human/non-human primate/mousecross-reactive RNAi triggers in human background, as determined bydual-luciferase reporter assay. Relative Rluc-F12 Expression AntisenseSEQ Sense SEQ 1 nM 0.1 nM AD Number Strand ID ID strand ID ID Average ±SD Average ± SD AD00459 AM00978-AS 451 AM00913-SS 837 0.871 ± 0.1380.956 ± 0.096 AD00460 AM00979-AS 452 AM00914-SS 838 0.878 ± 0.040 1.044± 0.127 AD00461 AM00980-AS 453 AM00915-SS 839 0.941 ± 0.163 1.003 ±0.052 AD00462 AM00981-AS 454 AM00916-SS 840 0.515 ± 0.068 0.584 ± 0.117AD00463 AM00982-AS 455 AM00917-SS 841 0.476 ± 0.014 0.552 ± 0.098AD00464 AM00983-AS 456 AM00918-SS 842 0.302 ± 0.072 0.442 ± 0.024AD00465 AM00984-AS 457 AM00919-SS 843 0.428 ± 0.042 0.517 ± 0.037AD00466 AM00985-AS 458 AM00920-SS 844 0.196 ± 0.016 0.282 ± 0.088AD00467 AM00986-AS 459 AM00921-SS 845 0.200 ± 0.034 0.303 ± 0.063AD00468 AM00987-AS 460 AM00922-SS 846 0.255 ± 0.032 0.300 ± 0.042AD00469 AM00988-AS 461 AM00923-SS 847 0.272 ± 0.060 0.411 ± 0.022AD00470 AM00989-AS 462 AM00924-SS 848 0.205 ± 0.011 0.328 ± 0.044AD00471 AM00990-AS 463 AM00925-SS 849 0.524 ± 0.105 0.667 ± 0.040AD00472 AM00991-AS 464 AM00926-SS 850 0.957 ± 0.062 0.909 ± 0.056AD00473 AM00992-AS 465 AM00927-SS 851 0.390 ± 0.093 0.502 ± 0.033AD00474 AM00993-AS 466 AM00928-SS 852 0.247 ± 0.083 0.420 ± 0.045AD00475 AM00994-AS 467 AM00929-SS 853 1.137 ± 0.029 1.049 ± 0.056AD00476 AM00995-AS 468 AM00930-SS 854 1.062 ± 0.221 0.873 ± 0.114AD00477 AM00996-AS 469 AM00931-SS 855 0.657 ± 0.022 0.881 ± 0.107AD00478 AM00997-AS 470 AM00932-SS 856 0.986 ± 0.118 0.856 ± 0.107AD00479 AM00998-AS 471 AM00933-SS 857 1.048 ± 0.023 0.920 ± 0.030AD00480 AM00999-AS 472 AM00934-SS 858 0.579 ± 0.026 0.608 ± 0.123AD00481 AM01000-AS 473 AM00935-SS 859 0.633 ± 0.081 0.779 ± 0.102AD00482 AM01001-AS 474 AM00936-SS 860 0.639 ± 0.100 0.708 ± 0.107AD00483 AM01002-AS 475 AM00937-SS 861 0.761 ± 0.100 0.694 ± 0.102AD00484 AM01003-AS 476 AM00938-SS 862 1.178 ± 0.074 1.168 ± 0.226AD00485 AM01004-AS 477 AM00939-SS 863 1.261 ± 0.218 0.964 ± 0.030AD00486 AM01005-AS 478 AM00940-SS 864 1.155 ± 0.278 1.084 ± 0.073AD00487 AM01006-AS 479 AM00941-SS 865 1.216 ± 0.081 1.161 ± 0.044AD00488 AM01007-AS 480 AM00942-SS 866 1.058 ± 0.051 1.112 ± 0.107AD00489 AM01008-AS 481 AM00943-SS 867 1.152 ± 0.189 0.980 ± 0.077AD00490 AM01009-AS 482 AM00944-SS 868 1.103 ± 0.273 1.138 ± 0.052

B) Mouse primary cell background. The same 32 siRNAs were screened forefficacy in a mouse background. Mouse primary hepatocytes were obtainedcryopreserved or pre-plated in 96-well plates (TRL Research, ResearchTriangle Park, N.C.). SiRNAs were transfected at two concentrations, 1nM and 0.1 nM, for 4 h with 0.6 μL per well of Lipofectamine RNAiMax(Life Technologies, Grand Island, N.Y.), after which fresh medium wassupplied. After 24 h cells were lysed for gene expression analysis usingthe TaqMan Gene Expression Cells-to-CT Kit (Life Technologies). Usingmouse-specific TaqMan gene expression assays (Life Technologies), F12expression relative to the endogenous control, β-actin, was determinedby qRT-PCR.

TABLE 7 Efficacy screen results of human/non-human primate/mousecross-reactive RNAi triggers in mouse background, as determined byqRT-PCR and comparative C_(T) analysis. Relative Mouse F12 Expression1.0 nM 0.1 nM error error AD Number Average low high Average low highAD00459 0.367 0.019 0.020 0.468 0.091 0.113 AD00460 0.494 0.080 0.0960.710 0.079 0.089 AD00461 0.353 0.053 0.063 0.673 0.090 0.104 AD004620.320 0.072 0.093 0.553 0.034 0.037 AD00463 0.377 0.016 0.017 0.7060.066 0.073 AD00464 0.232 0.044 0.055 0.418 0.087 0.110 AD00465 0.3350.033 0.037 0.691 0.092 0.106 AD00466 0.271 0.018 0.019 0.406 0.0670.080 AD00467 0.070 0.014 0.018 0.204 0.008 0.009 AD00468 0.156 0.0310.039 0.259 0.038 0.044 AD00469 0.157 0.020 0.024 0.335 0.028 0.031AD00470 0.228 0.030 0.035 0.320 0.042 0.048 AD00471 0.347 0.031 0.0350.376 0.082 0.106 AD00472 0.496 0.043 0.048 0.579 0.129 0.166 AD004730.257 0.019 0.020 0.518 0.107 0.136 AD00474 0.223 0.021 0.023 0.2280.033 0.038 AD00475 1.024 0.177 0.214 0.909 0.069 0.075 AD00476 1.1100.029 0.030 1.160 0.118 0.132 AD00477 0.713 0.034 0.036 0.934 0.0420.044 AD00478 1.187 0.075 0.080 1.114 0.086 0.093 AD00479 1.168 0.1170.130 0.889 0.076 0.083 AD00480 0.380 0.078 0.098 0.489 0.049 0.055AD00481 0.528 0.115 0.147 0.607 0.105 0.128 AD00482 0.359 0.050 0.0580.367 0.065 0.079 AD00483 0.307 0.021 0.022 0.493 0.105 0.133 AD004840.980 0.032 0.033 0.640 0.167 0.226 AD00485 0.218 0.026 0.029 0.1790.033 0.040 AD00486 0.208 0.006 0.006 0.173 0.019 0.021 AD00487 0.2330.018 0.019 0.185 0.018 0.020 AD00488 0.223 0.030 0.035 0.267 0.0310.035 AD00489 0.169 0.023 0.027 0.180 0.014 0.015 AD00490 0.271 0.0580.075 0.139 0.016 0.018

C) EC₅₀ calculation. Six candidate RNAi triggers were further assessed.Ten-point EC₅₀ curves were generated using the same cells andtransfection conditions, as in A) above, with siRNA concentrationsranging from 150 fM to 3 nM. Each of these six F12 RNAi triggers wasfurther modified and synthesized as a corresponding UNA-containing RNAitrigger. All modified RNAi triggers were examined by in vitro knockdownanalysis by both 3-concentration analysis (0.02, 0.2 and 2 nM) andten-point EC₅₀ determination.

TABLE 8 EC₅₀ values (nM) determined in the human background for theindicated RNAi triggers. Duplex ID No. EC₅₀ (nM) AD00466 0.019 AD00903AM01622-AS 597 AM00920-SS 844 0.049 AD00904 AM01623-AS 598 AM00920-SS844 0.057 AD00915 AM01621-AS 596 AM01614-SS 983 0.049 AD00916 AM00985-AS458 AM01614-SS 983 0.189 AD00467 0.133 AD00905 AM01624-AS 599 AM00921-SS845 0.076 AD00906 AM01625-AS 600 AM00921-SS 845 0.104 AD00468 0.081AD00907 AM01626-AS 601 AM00922-SS 846 0.143 AD00908 AM01627-AS 602AM00922-SS 846 0.077 AD00469 0.070 AD00909 AM01629-AS 604 AM00923-SS 8470.049 AD00910 AM01630-AS 605 AM00923-SS 847 0.037 AD00917 AM01628-AS 603AM01618-SS 987 0.089 AD00918 AM00988-AS 461 AM01618-SS 987 0.103 AD004700.145 AD00911 AM01631-AS 606 AM00924-SS 848 0.982 AD00912 AM01632-AS 607AM00924-SS 848 0.153 AD00474 0.261 AD00913 AM01633-AS 608 AM00928-SS 8520.132 AD00914 AM01634-AS 609 AM00928-SS 852 0.175

D) Human/non-human primate-specific RNAi triggers. Additional sequencesidentified as human and non-human primate, but not mouse, cross-reactiveby in silico analysis were additionally screened in human background.The top twelve sequences were screened using the procedure describedabove, with full 10-point dose response curves and EC₅₀ determinationperformed for the six most active RNAi triggers.

TABLE 9 Efficacy screen of human/non-human primate-specific RNAitriggers and EC₅₀ values (nM). Relative R_(luc)-F12 Expression 1 nM 0.1nM SEQ ID pair Average ± SD Average ± SD EC₅₀ (nM) 1940/2053 0.172 ±0.018 0.314 ± 0.007 0.026 1941/2054 0.218 ± 0.021 0.312 ± 0.029 0.0131943/2056 0.139 ± 0.016 0.245 ± 0.060 0.027 1944/2054 0.258 ± 0.0070.314 ± 0.037 1946/2059 0.166 ± 0.016 0.225 ± 0.022 0.017 1947/20600.273 ± 0.029 0.382 ± 0.071 1951/2064 0.536 ± 0.011 1.108 ± 0.2101966/2079 0.745 ± 0.080 0.963 ± 0.051 1971/2084 0.714 ± 0.018 0.853 ±0.088 1982/2095 0.519 ± 0.065 0.680 ± 0.081 1983/2096 0.454 ± 0.0030.622 ± 0.071 2013/2126 0.579 ± 0.006 0.778 ± 0.108

Example 4. In Vivo Analysis of RNAi Trigger Efficacy in Wild-Type Miceor Rates

A) Administration and sample collection. In order to evaluate theefficacy of F12 RNAi triggers in vivo, wild-type mice or rats were used.RNAi triggers were dosed either by intravenous (IV) or subcutaneous (SQ)injection. Cholesterol-targeted RNAi triggers were administered to miceor rats using MLP delivery polymer on day 1. Each rodent received anintravenous (IV) injection into the tail vein of 200-250 μL solutioncontaining a dose of RNAi trigger+MLP delivery polymer (1:1 w/w RNAitrigger: MLP delivery polymer in most cases). Alkyne-containing RNAitriggers were administered to mice after conjugation with targetingpolymer by either IV or SQ injection. Galactose-cluster containing RNAitriggers were most often dosed SQ, but could also be dosed incombination with MLP delivery polymer. When possible, baseline(pre-treatment) samples were taken from the mice pre-injection betweendays 7 and injection on day 1. Post injection serum samples were takenfrom the mice days 4, 8, and weekly up to day 71. In some mice, livertissue was harvested for RNA isolation on days indicated.

B) Factor 12 serum protein levels. F12 protein (mF12) levels in serumwere monitored by assaying serum from the mice using an ELISA for mF12(Molecular Innovations) or an internally developed mF12 alphaLISA®(Perkin Elmer) until expression levels returned to baseline. For animalswith baseline samples, mF12 level for each animal at a respective timepoint was divided by the pre-treatment level of expression in thatanimal to determine the ratio of expression “normalized topre-treatment”. Expression at a specific time point was then normalizedto the saline control group by dividing the “normalized to daypre-treatment” ratio for an individual animal by the mean “normalized today pre-treatment” ratio of all mice in the saline control group. Thisresulted in expression for each time point normalized to that in thecontrol group. For samples without baseline samples, expression at aspecific bleed date was normalized to the mean of the saline controlgroup for that same date. For all studies, experimental error is givenas standard deviation.

Example 5. In Vivo Screening F12 RNAi Triggers and Time Course of F12Knockdown

Wild-type mice were dosed either IV (cholesterol-conjugated RNAi triggerwith delivery polymer) or subcutaneous (SQ)(galactose-cluster-conjugated RNAi trigger), and mF12 levels weremonitored as described above. Maximum knockdown (nadir) of mF12 for eachRNAi trigger examined is shown in Table 10. Nadir was between days 4-22.Relative serum mF12 levels following administration of RNAi triggersover the time of the experiment is shown for select RNAi triggers tested(see Tables 11, 12, 13, 14, 15 and 16, FIG. 1). A decrease in F12 serumprotein level of greater than 98% was obtained following administrationof all RNAi triggers tested, with AD00900 showing greatest duration ofknockdown (>87% knockdown at day 36). RD10694, a known mouse Factor VII(mF7) RNAi trigger sequence, was used as a control RNAi trigger in theseexperiments (Table 10).

TABLE 10 Relative serum F12 protein levels in mice following intravenousadministration of the indicated F12 RNAi trigger with MLP (deliverypolymer) or subcutaneous administration of the indicated F12 RNAitrigger (no delivery polymer). mF12 levels were normalized topre-treatment and saline control. (F12 RNAi trigger Duplex ID No. withsense strand and antisense strand ID nos.) RNAi Delivery DuplexAntisense SEQ Sense SEQ trigger Polymer Relative ID No. Strand ID IDStrand ID ID (mg/kg) (mg/kg) Factor 12 AD00897 AM00985-AS 458 AM01613-SS982 8 8 0.007 AD00898 AM00986-AS 459 AM01615-SS 984 8 8 0.007 AD00899AM00987-AS 460 AM01616-SS 985 8 8 0.009 AD00900 AM00988-AS 461AM01617-SS 986 8 8 0.007 AD00901 AM00989-AS 462 AM01619-SS 988 8 8 0.020AD00902 AM00993-AS 466 AM01620-SS 989 8 8 0.012 AD00998 AM01622-AS 597AM01613-SS 982 2 2 0.284 AD00999 AM01624-AS 599 AM01615-SS 984 2 2 0.175AD01000 AM01626-AS 601 AM01616-SS 985 2 2 0.052 AD01001 AM01629-AS 604AM01617-SS 986 2 2 0.048 AD01002 AM01631-AS 606 AM01619-SS 988 2 2 0.253AD01003 AM01633-AS 608 AM01620-SS 989 2 2 0.132 AD01004 AM01623-AS 598AM01613-SS 982 2 2 0.136 AD01005 AM01625-AS 600 AM01615-SS 984 2 2 0.464AD01006 AM01627-AS 602 AM01616-SS 985 2 2 0.268 AD01007 AM01630-AS 605AM01617-SS 986 2 2 0.127 AD01008 AM01632-AS 607 AM01619-SS 988 2 2 0.263AD01009 AM01634-AS 609 AM01620-SS 989 2 2 0.228 AD01109 AM01903-AS 610AM01616-SS 985 0.5 2 0.243 AD01110 AM01904-AS 611 AM01905-SS 990 0.5 20.263 AD01111 AM01906-AS 612 AM01617-SS 986 0.5 2 0.159 AD01112AM01907-AS 613 AM01908-SS 991 0.5 2 0.293 AD01113 AM01909-AS 614AM01620-SS 989 0.5 2 0.289 AD01114 AM01910-AS 615 AM01911-SS 992 0.5 20.645 AD01115 AM01918-AS 619 AM01905-SS 990 0.5 2 0.202 AD01116AM01919-AS 620 AM01908-SS 991 0.5 2 0.204 AD01117 AM01920-AS 621AM01911-SS 992 0.5 2 0.266 AD01118 AM01927-AS 625 AM01924-SS 994 0.5 20.275 AD01119 AM01928-AS 626 AM01924-SS 994 0.5 2 0.442 AD01120AM01929-AS 627 AM01924-SS 994 0.5 2 0.374 AD01121 AM01931-AS 629AM01932-SS 996 0.5 2 0.284 AD01122 AM01915-AS 616 AM01617-SS 986 0.5 20.144 AD01123 AM01916-AS 617 AM01908-SS 991 0.5 2 0.226 AD01124AM01917-AS 618 AM01908-SS 991 0.5 2 0.158 AD01125 AM01921-AS 622AM01922-SS 993 0.5 2 0.271 AD01126 AM01923-AS 623 AM01924-SS 994 0.5 20.247 AD01127 AM01925-AS 624 AM01926-SS 995 0.5 2 0.526 AD01128AM01930-AS 628 AM01932-SS 996 0.5 2 0.332 AD01181 AM01996-AS 630AM01995-SS 997 0.5 2 0.100 AD01182 AM01997-AS 631 AM01995-SS 997 0.5 20.167 AD01251 AM01629-AS 604 AM02084-SS 1000 0.5 4 0.724 AD01303AM02165-AS 637 AM02168-SS 1002 2 2 0.233 AD01307 AM02165-AS 637AM02169-SS 1003 2 2 0.096 AD01312 AM02171-AS 640 AM02173-SS 1004 2 20.194 AD01313 AM02172-AS 641 AM02174-SS 1005 2 2 0.173 AD01327AM02165-AS 637 AM02196-SS 1006 2 2 0.083 AD01367 AM02197-AS 642AM02269-SS 1014 0.5 2 0.378 AD01368 AM02198-AS 643 AM02270-SS 1015 0.5 20.516 AD01369 AM02199-AS 644 AM02271-SS 1016 0.5 2 0.279 AD01370AM02172-AS 641 AM02272-SS 1017 0.5 2 0.366 AD01371 AM02200-AS 645AM02273-SS 1018 0.5 2 0.476 AD01372 AM02201-AS 646 AM02274-SS 1019 0.5 20.162 AD01373 AM02208-AS 647 AM02275-SS 1020 0.5 2 0.187 AD01394AM02331-AS 648 AM02330-SS 1023 2 2 0.086 AD01395 AM02332-AS 649AM02330-SS 1023 2 2 0.089 AD01396 AM02333-AS 650 AM02330-SS 1023 2 20.409 AD01397 AM02334-AS 651 AM02330-SS 1023 2 2 0.574 AD01398AM02335-AS 652 AM02330-SS 1023 2 2 0.063 AD01399 AM02336-AS 653AM02330-SS 1023 2 2 0.765 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AM03482-SS 1270 30.915 AD02707 AM03483-AS 826 AM03402-SS 1232 3 0.245 AD02708 AM03484-AS827 AM03402-SS 1232 3 0.121 AD02709 AM03485-AS 828 AM03402-SS 1232 30.974 AD02774 AM03589-AS 833 AM03591-SS 1290 3 0.625 AD02775 AM03590-AS834 AM03591-SS 1290 3 0.649 AD02776 AM03590-AS 834 AM03592-SS 1291 30.565 AD02777 AM03157-AS 791 AM03588-SS 1289 3 0.277 AD02803 AM03157-AS791 AM03629-SS 1293 3 0.377 AD02804 AM03157-AS 791 AM03630-SS 1294 30.337 AD02806 AM03157-AS 791 AM03631-SS 1295 3 0.317 AD02807 AM03157-AS791 AM03632-SS 1296 3 0.205 AD02808 AM03157-AS 791 AM03633-SS 1297 30.519 AD02809 AM03410-AS 820 AM03634-SS 1298 3 0.610 AD02810 AM03157-AS791 AM03635-SS 1299 3 0.268 AD02811 AM03157-AS 791 AM03636-SS 1300 30.242 AD02812 AM03157-AS 791 AM03637-SS 1301 3 0.238 AD02813 AM03410-AS820 AM03638-SS 1302 3 0.759 AD02814 AM03157-AS 791 AM03639-SS 1303 30.223 AD02815 AM03157-AS 791 AM03640-SS 1304 3 0.212 AD02816 AM03157-AS791 AM03641-SS 1305 3 0.455 AD02817 AM03410-AS 820 AM03642-SS 1306 30.524 AD02822 AM03581-AS 830 AM03653-SS 1359 3 0.164 AD02823 AM03157-AS791 AM03653-SS 1359 3 0.285 AD02824 AM03157-AS 791 AM03654-SS 1360 30.152 AD02867 AM03157-AS 791 AM03703-SS 1363 3 0.036 AD02868 AM03157-AS791 AM03704-SS 1364 3 0.034 AD02872 AM03417-AS 823 AM03413-SS 1242 30.170

TABLE 11 Serum F12 protein levels in wild-type mice followingadministration of 8 mg/kg RNAi trigger with 8 mg/kg MLP deliverypolymer. mF12 levels were normalized to pre-treatment and salinecontrol. F12 levels Day day day day day day day treatment −4 4 8 15 2229 36 Saline 1.000 1.000 ± 0.158 1.000 ± 0.133 1.000 ± 0.239 1.000 ±0.179 1.000 ± 0.131 1.000 ± 0.303 RD 10694 1.000 1.075 ± 0.032  1.26 ±0.071 0.778 ± 0.60  0.977 ± 0.037 0.778 ± 0.060 1.030 ± 0.102 (control)AD00897 1.000 0.092 ± 0.006 0.007 ± 0.001 0.007 ± 0.005 0.031 ± 0.0150.148 ± 0.081 0.639 ± 0.186 AD00898 1.000 0.104 ± 0.013 0.007 ± 0.0020.024 ± 0.004 0.142 ± 0.039 0.571 ± 0.165 0.907 ± 0.147 AD00899 1.0000.090 ± 0.004 0.009 ± 0.000 0.041 ± 0.019 0.114 ± 0.070 0.262 ± 0.0550.580 ± 0.096 AD00900 1.000 0.084 ± 0.012 0.007 ± 0.002 0.014 ± 0.0050.016 ± 0.003 0.033 ± 0.010 0.123 ± 0.025 AD00901 1.000 0.101 ± 0.0140.020 ± 0.004 0.043 ± 0.005 0.068 ± 0.019 0.176 ± 0.059 0.491 ± 0.097AD00902 1.000 0.111 ± 0.022 0.012 ± 0.005 0.022 ± 0.007 0.040 ± 0.0240.132 ± 0.054 0.441 ± 0.131 F12 levels day day day day day treatment 4350 57 63 71 Saline 1.000 ± 0.150 1.000 ± 0.076 1.000 ± 0.047 1.000 ±0.099 1.000 ± 0.100 RD 10694 0.846 ± 0.067 0.832 ± 0.221 0.968 ± 0.0700.916 ± 0.064 0.936 ± 0.062 (control) AD00897 0.875 ± 0.172 0.873 ±0.134 0.924 ± 0.107 0.952 ± 0.130 1.013 ± 0.195 AD00898 1.098 ± 0.0840.997 ± 0.079 1.073 ± 0.051 1.077 ± 0.041 1.059 ± 0.063 AD00899 0.791 ±0.067 0.905 ± 0.069 0.959 ± 0.053 0.978 ± 0.079 1.059 ± 0.091 AD009000.207 ± 0.038 0.331 ± 0.068 0.569 ± 0.104 0.784 ± 0.027 0.961 ± 0.094AD00901 0.630 ± 0.147 0.566 ± 0.369 0.871 ± 0.119 0.909 ± 0.084 1.083 ±0.120 AD00902 0.647 ± 0.194 0.778 ± 0.167 0.887 ± 0.139 0.967 ± 0.1481.055 ± 0.166

TABLE 12 Serum F12 protein levels in C57/B6 mice followingadministration of 2 mg/kg canonical or UNA-containing RNAi triggers with2 mg/kg MLP delivery polymer. mF12 levels were normalized topre-treatment and saline control. Day 3 Day 8 Day 15 Day 22 Day 29 Day36 Day 43 Day 50 Day 57 saline 1.00 ± 0.09 1.00 ± 0.13 1.00 ± 0.12 1.00± 0.07 1.00 ± 0.26 1.00 ± 0.10 1.00 ± 0.20 1.00 ± 0.11 1.00 ± 0.04RD10694 0.93 ± 0.06 1.03 ± 0.05 0.97 ± 0.05 0.95 ± 0.08 1.44 ± 0.09 1.09± 0.58 AD00897 0.17 ± 0.05 0.07 ± 0.00 0.27 ± 0.03 0.67 ± 0.13 1.07 ±0.27 1.44 ± 0.27 AD00898 0.21 ± 0.01 0.26 ± 0.16 0.66 ± 0.19 0.89 ± 0.061.23 ± 0.45 1.14 ± 0.77 AD00899 0.18 ± 0.01 0.10 ± 0.04 0.23 ± 0.08 0.38± 0.11 1.09 ± 0.15 1.25 ± 0.61 0.98 ± 0.07 0.92 ± 0.13 0.97 ± 0.22AD00900 0.21 ± 0.03 0.09 ± 0.04 0.20 ± 0.06 0.35 ± 0.09 1.01 ± 0.21 1.11± 0.13 0.87 ± 0.09 0.93 ± 0.03 0.89 ± 0.28 AD00901 0.35 ± 0.03 0.37 ±0.07 0.55 ± 0.04 0.74 ± 0.03 1.72 ± 0.11 0.65 ± 0.09 AD00902 0.21 ± 0.010.10 ± 0.03 0.22 ± 0.04 0.42 ± 0.09 0.84 ± 0.02 1.15 ± 0.34 AD00897 0.28± 0.04 0.31 ± 0.11 0.70 ± 0.11 1.00 ± 0.08 1.52 ± 0.48 1.09 ± 0.77AD00999 0.17 ± 0.03 0.19 ± 0.03 0.71 ± 0.05 0.98 ± 0.02 1.58 ± 0.03 1.53± 0.42 AD01000 0.17 ± 0.02 0.05 ± 0.01 0.18 ± 0.03 0.40 ± 0.10 0.66 ±0.05 0.74 ± 0.12 0.91 ± 0.06 0.92 ± 0.11 1.10 ± 0.13 AD01001 0.16 ± 0.020.05 ± 0.02 0.12 ± 0.04 0.23 ± 0.08 0.63 ± 0.17 0.85 ± 0.20 0.73 ± 0.130.83 ± 0.25 1.03 ± 0.23 AD01002 0.25 ± 0.04 0.25 ± 0.09 0.38 ± 0.09 0.64± 0.08 1.07 ± 0.37 0.96 ± 0.66 AD01003 0.29 ± 0.06 0.13 ± 0.07 0.26 ±0.10 0.58 ± 0.21 1.27 ± 0.05 1.67 ± 0.13 AD01004 0.29 ± 0.02 0.14 ± 0.020.24 ± 0.07 0.52 ± 0.07 0.93 ± 0.19 1.48 ± 0.14 AD01005 0.39 ± 0.06 0.46± 0.17 0.89 ± 0.20 1.11 ± 0.08 1.33 ± 0.32 1.16 ± 0.61 AD01006 0.35 ±0.02 0.27 ± 0.14 0.46 ± 0.25 0.66 ± 0.25 1.27 ± 0.26 1.76 ± 0.17 0.93 ±0.06 0.93 ± 0.01 0.99 ± 0.29 AD01007 0.27 ± 0.02 0.13 ± 0.01 0.15 ± 0.030.22 ± 0.05 0.58 ± 0.10 0.69 ± 0.15 0.61 ± 0.11 0.85 ± 0.04  0.9 ± 0.26AD01008 0.36 ± 0.04 0.26 ± 0.08 0.35 ± 0.09 0.53 ± 0.14 1.02 ± 0.10 1.10± 0.61 AD01109 0.35 ± 0.09 0.23 ± 0.09 0.39 ± 0.17 0.73 ± 0.16 1.10 ±0.41 1.29 ± 0.23

TABLE 13 Relative serum F12 protein levels in C57/B6 mice followingadministration of 0.5 mg/kg modified F12 RNAi triggers with 2 mg/kg MLPdelivery polymer. mF12 levels were normalized to pre-treatment andsaline control. Treatment Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Day 43Saline 1.00 ± 0.07 1.00 ± 0.06 1.00 ± 0.39 1.00 ± 0.17 1.00 ± 0.08 1.00± 0.07 1.00 ± 0.03 AD01000 0.26 ± 0.07 0.34 ± 0.15 1.25 ± 0.38 0.79 ±0.14 0.89 ± 0.05 0.95 ± 0.12 AD01001 0.18 ± 0.02 0.17 ± 0.02 0.34 ± 0.050.35 ± 0.10 0.62 ± 0.02 0.85 ± 0.05 1.03 ± 0.10 AD01003 0.19 ± 0.01 0.20± 0.03 0.62 ± 0.02 0.56 ± 0.16 0.86 ± 0.09 0.97 ± 0.14 AD01007 0.27 ±0.09 0.15 ± 0.08 0.39 ± 0.06 0.40 ± 0.01 0.76 ± 0.13 0.98 ± 0.26 1.25 ±0.49 AD01115 0.20 ± 0.12 0.28 ± 0.18 0.95 ± 0.62 0.92 ± 0.48 1.19 ± 0.621.32 ± 0.65 AD01116 0.23 ± 0.12 0.20 ± 0.14 0.45 ± 0.33 0.54 ± 0.37 0.74± 0.37 1.03 ± 0.52 1.20 ± 0.79 AD01117 0.27 ± 0.03 0.29 ± 0.03 0.73 ±0.03 0.73 ± 0.03 0.96 ± 0.11 1.09 ± 0.07 AD01118 0.28 ± 0.11 0.27 ± 0.110.55 ± 0.22 0.63 ± 0.10 0.84 ± 0.18 1.15 ± 0.29 0.85 ± 0.18 AD01124 0.23± 0.09 0.16 ± 0.09 0.38 ± 0.19 0.40 ± 0.18 0.68 ± 0.28 0.98 ± 0.26 1.09± 0.38 AD01125 0.27 ± 0.12 0.33 ± 0.12 0.96 ± 0.09 0.85 ± 0.04 1.02 ±0.10 1.16 ± 0.13 AD01126 0.25 ± 0.02 0.30 ± 0.05 0.73 ± 0.10 0.68 ± 0.060.91 ± 0.06 1.12 ± 0.15 1.20 ± 0.07 AD01127 0.55 ± 0.19 0.53 ± 0.25 1.24± 0.25 0.85 ± 0.04 1.09 ± 0.14 1.13 ± 0.08

TABLE 14 Relative serum F12 protein levels in C57/B6 mice followingadministration of 0.5 mg/kg modified F12 RNAi triggers with 2 mg/kg MLPdelivery polymer. mF12 levels were normalized to pre-treatment andsaline control. Treatment Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Day 43Day 53 Saline 1.00 ± 0.12 1.00 ± 0.33 1.00 ± 0.07 1.00 ± 0.08 1.00 ±0.06 1.00 ± 0.05 1.00 ± 0.07 1.00 ± 0.09 AD01001 0.13 ± 0.03 0.09 ± 0.040.20 ± 0.09 0.32 ± 0.11 0.55 ± 0.09 0.73 ± 0.09 0.84 ± 0.12 0.93 ± 0.07AD01007 0.39 ± 0.25 0.38 ± 0.29 0.59 ± 0.35 0.71 ± 0.37 0.83 ± 0.21 1.11± 0.32 0.90 ± 0.12 1.02 ± 0.16 AD01111 0.17 ± 0.01 0.16 ± 0.05 0.37 ±0.08 0.54 ± 0.16 0.89 ± 0.09 1.02 ± 0.10 0.93 ± 0.06 0.96 ± 0.08 AD011120.29 ± 0.21 0.34 ± 0.32 0.63 ± 0.35 0.61 ± 0.13 1.02 ± 0.17 1.12 ± 0.121.03 ± 0.13 1.03 ± 0.10 AD01119 0.44 ± 0.10 0.46 ± 0.12 0.64 ± 0.09 1.02± 0.11 0.95 ± 0.02 1.00 ± 0.08 0.90 ± 0.08 0.93 ± 0.05 AD01120 0.37 ±0.18 0.50 ± 0.20 0.75 ± 0.24 0.94 ± 0.12 1.00 ± 0.06 0.96 ± 0.09 0.98 ±0.09 0.93 ± 0.09 AD01121 0.44 ± 0.11 0.28 ± 0.18 0.50 ± 0.14 0.65 ± 0.120.92 ± 0.10 1.02 ± 0.06 0.91 ± 0.10 0.95 ± 0.01 AD01122 0.14 ± 0.04 0.15± 0.08 0.29 ± 0.09 0.43 ± 0.05 0.73 ± 0.12 0.90 ± 0.02 0.82 ± 0.08 0.97± 0.10 AD01123 0.23 ± 0.04 0.26 ± 0.07 0.48 ± 0.11 0.67 ± 0.10 0.90 ±0.11 0.91 ± 0.15 0.90 ± 0.06 1.08 ± 0.11 AD01128 0.33 ± 0.11 0.33 ± 0.170.42 ± 0.37 0.86 ± 0.38 0.96 ± 0.11 0.98 ± 0.04 0.92 ± 0.09 0.98 ± 0.19

TABLE 15 Relative serum F12 protein levels in C57/B6 mice followingadministration of 0.5 mg/kg modified F12 RNAi triggers with 2 mg/kg MLPdelivery polymer. mF12 levels were normalized to pre-treatment andsaline control. Treatment Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Day 43Saline 1.00 ± 0.15 1.00 ± 0.13 1.00 ± 0.07 1.00 ± 0.11 1.00 ± 0.10 1.00± 0.08 1.00 ± 0.15 AD01000 0.24 ± 0.11 0.29 ± 0.18 0.50 ± 0.20 0.68 ±0.18 0.95 ± 0.13 0.89 ± 0.06 0.97 ± 0.09 AD01003 0.19 ± 0.04 0.25 ± 0.090.43 ± 0.13 0.64 ± 0.11 0.86 ± 0.03 0.86 ± 0.06 1.00 ± 0.12 AD01109 0.24± 0.06 0.31 ± 0.16 0.74 ± 0.15 0.79 ± 0.09 0.86 ± 0.12 0.87 ± 0.05 0.92± 0.14 AD01110 0.26 ± 0.03 0.34 ± 0.07 0.78 ± 0.01 0.80 ± 0.06 0.94 ±0.04 0.85 ± 0.09 0.82 ± 0.09 AD01113 0.29 ± 0.10 0.30 ± 0.04 0.71 ± 0.050.88 ± 0.11 1.02 ± 0.08 1.02 ± 0.09 0.94 ± 0.08 AD01114 0.64 ± 0.25 0.91± 0.32 1.05 ± 0.15 1.02 ± 0.08 0.85 ± 0.06 0.89 ± 0.12 0.94 ± 0.04

TABLE 16 Relative serum F12 protein levels in C57/B6 mice followingadministration of 0.5 mg/kg modified F12 RNAi triggers with 2 mg/kg MLPdelivery polymer. mF12 levels were normalized to pre-treatment andsaline control. Day treatment 4 8 15 22 29 36 43 50 57 Saline 1.00 ±0.13 1.00 ± 0.10 1.00 ± 0.07 1.00 ± 0.08 1.00 ± 0.04 1.00 ± 0.12 1.00 ±0.09 1.00 ± 0.11 1.00 ± 0.11 AD01001 0.12 ± 0.02 0.08 ± 0.02 0.17 ± 0.050.36 ± 0.07 0.46 ± 0.06 0.69 ± 0.15 0.83 ± 0.15 0.89 ± 0.11 1.05 ± 0.28AD01126 0.34 ± 0.16 0.39 ± 0.16 0.60 ± 0.17 0.88 ± 0.04 0.87 ± 0.22 0.95± 0.10 0.94 ± 0.09 0.95 ± 0.11 1.00 ± 0.08 AD01181 0.16 ± 0.03 0.15 ±0.03 0.29 ± 0.09 0.51 ± 0.09 0.69 ± 0.08 0.69 ± 0.08 0.90 ± 0.10 0.87 ±0.15 0.97 ± 0.14 AD01007 0.19 ± 0.02 0.16 ± 0.04 0.30 ± 0.07 0.49 ± 0.110.64 ± 0.07 0.77 ± 0.07 0.87 ± 0.15 0.92 ± 0.04 0.88 ± 0.11 AD01118 0.22± 0.07 0.18 ± 0.09 0.37 ± 0.16 0.52 ± 0.19 0.69 ± 0.17 0.76 ± 0.16 0.90± 0.10 0.96 ± 0.11 0.94 ± 0.18 AD01182 0.19 ± 0.04 0.17 ± 0.07 0.31 ±0.10 0.50 ± 0.15 0.67 ± 0.15 0.86 ± 0.16 0.85 ± 0.18 0.92 ± 0.09 0.90 ±0.13

Example 6. In Vivo Dose Response of Select F12 RNAi Triggers and TimeCourse of F12 Knockdown

To further characterize in vivo activity of select RNAi triggers,activity of multiple dose levels were examined in a single experiment.For studies with MLP delivery polymer (IV), both the amount of RNAitrigger dosed and the amount of delivery polymer was adjusted, so thatthe dose ratio varied. Dosing and mF12 levels were monitored asdescribed above. Relative serum mF12 levels following administration ofRNAi triggers over the time of the experiment is shown (see Tables 17and 18, FIGS. 2 and 3).

Example 7. In Vivo Multiple Dose Studies of Select F12 RNAi Triggers andTime Course of F12 Knockdown

Select triggers were chosen to examine using multiple dose dosingschemes. The most commonly used dosing scheme was three weekly doses andmonitoring mF12 levels as described above. This multiple dose dosingscheme was used most often for SQ-delivered triggers. Relative serummF12 levels following administration of RNAi triggers over time is shownin FIG. 4.

TABLE 17 Serum F12 protein levels in C57/B6 mice followingadministration of 0.5, 1, or 2 mg/kg UNA-containing RNAi triggers with 2mg/kg MLP delivery polymer. mF12 levels were normalized to pre-treatmentand saline control [trigger] Treatment (mg/kg) Day 4 Day 8 Day 15 Day 22Day 29 Saline 1.00 ± 0.25 1.00 ± 0.28 1.00 ± 0.13 1.00 ± 0.39 1.00 ±0.19 AD01000 2 0.14 ± 0.01 0.06 ± 0.04 0.19 ± 0.07 0.67 ± 0.27 0.72 ±0.17 1 0.18 ± 0.03 0.13 ± 0.08 0.29 ± 0.11 0.74 ± 0.30 0.81 ± 0.05 0.50.21 ± 0.06 0.17 ± 0.08 0.38 ± 0.15 0.90 ± 0.10 0.89 ± 0.13 AD01001 20.13 ± 0.03 0.03 ± 0.01 0.03 ± 0.01 0.22 ± 0.11 0.29 ± 0.10 1 0.15 ±0.01 0.06 ± 0.03 0.05 ± 0.02 0.40 ± 0.12 0.54 ± 0.15 0.5 0.18 ± 0.030.13 ± 0.06 0.24 ± 0.10 0.55 ± 0.19 0.57 ± 0.12 AD01003 2 0.18 ± 0.030.06 ± 0.02 0.19 ± 0.04 0.63 ± 0.13 0.80 ± 0.15 1 0.21 ± 0.03 0.10 ±0.01 0.28 ± 0.06 0.87 ± 0.15 0.78 ± 0.13 0.5 0.29 ± 0.10 0.19 ± 0.120.42 ± 0.21 1.12 ± 0.33 1.11 ± 0.46 Treatment Day 36 Day 43 Day 50 Day57 Saline 1.00 ± 0.12 1.00 ± 0.31 1.00 ± 0.16 1.00 ± 0.15 AD01000 0.81 ±0.13 1.16 ± 0.16 0.86 ± 0.15 1.30 ± 0.13 0.81 ± 0.10 1.12 ± 0.24 AD010010.52 ± 0.12 0.80 ± 0.17 0.75 ± 0.26 0.93 ± 0.08 0.65 ± 0.13 1.00 ± 0.210.90 ± 0.17 0.93 ± 0.14 0.72 ± 0.08 1.02 ± 0.23 0.93 ± 0.16 0.94 ± 0.07AD01003 0.84 ± 0.17 1.05 ± 0.30 0.95 ± 0.08 1.34 ± 0.19 0.99 ± 0.27 1.34± 0.33

TABLE 18 Relative serum F12 protein levels in mice followingadministration of 2 or 4 mg/kg dose of AD01001 RNAi triggers with 1, 2,4 or 8 mg/kg of MLP delivery polymer. F12 levels were normalized topre-treatment and saline control. trigger MLP Day treatment mg/kg mg/kg4 8 15 22 29 Saline 1.00 ± 0.03 1.00 ± 0.05 1.00 ± 0.03 1.00 ± 0.01 1.00± 0.06 AD01001 4 8 0.07 ± 0.01 0.01 ± 0.00 0.01 ± 0.00 0.03 ± 0.01 0.06± 0.02 4 4 0.08 ± 0.05 0.05 ± 0.06 0.09 ± 0.14 0.15 ± 0.20 0.24 ± 0.22 42 0.09 ± 0.02 0.08 ± 0.03 0.16 ± 0.08 0.28 ± 0.12 0.42 ± 0.14 2 4 0.06 ±0.01 0.04 ± 0.01 0.05 ± 0.03 0.11 ± 0.06 0.23 ± 0.10 2 2 0.10 ± 0.020.07 ± 0.02 0.12 ± 0.05 0.24 ± 0.06 0.39 ± 0.10 2 1 0.27 ± 0.13 0.35 ±0.16 0.41 ± 0.03 0.72 ± 0.17 0.75 ± 0.12 Day treatment 36 43 50 57Saline 1.00 ± 0.19 1.00 ± 0.06 1.00 ± 0.19 1.00 ± 0.06 AD01001 0.18 ±0.05 0.32 ± 0.08 0.54 ± 0.06 0.78 ± 0.12 0.36 ± 0.25 0.52 ± 0.19 0.75 ±0.14 0.73 ± 0.09 0.65 ± 0.18 0.69 ± 0.09 0.79 ± 0.19 0.79 ± 0.06 0.38 ±0.12 0.54 ± 0.16 0.76 ± 0.11 0.74 ± 0.04 0.58 ± 0.11 0.75 ± 0.08 0.85 ±0.11 0.79 ± 0.07 0.93 ± 0.13 0.93 ± 0.16 0.74 ± 0.13 0.79 ± 0.13

Example 8. Liver F12 mRNA Levels

At the time of euthanization, part or all of the mouse liver wastransferred to an appropriate volume of TRI Reagent RT (MolecularResearch Center, Inc., Cincinnati, Ohio). Total RNA was isolatedfollowing the manufacturer's recommended protocol. Briefly, liversections in TRI Reagent RT were treated with a tissue homogenizer forapproximately 30 sec. 1 mL homogenate was added to 50 μL of4-bromoanisole, mixed, and phases were separated by centrifugation.0.25-0.5 mL of aqueous phase was removed, precipitated with isopropylalcohol, and centrifuged. The resultant pellet was washed with 75%ethanol and suspended in 0.3-0.7 mL nuclease-free water.

Total RNA (˜500 ng) was reverse transcribed using the High Capacity cDNAReverse Transcription Kit (Life Technologies, Grand Island, N.Y.). ThecDNA was then diluted 1:5 and multiplex RT-qPCR was performed using 5′exonuclease chemistry with the commercially available FAM-labeled assayfor mouse Factor 12 (Assay ID#Mm00491349_m1, Life Technologies), theVIC-labeled endogenous control assay for mouse beta-actin (LifeTechnologies) and VeriQuest Master Mix (Affymetrix, Santa Clara,Calif.). Gene expression data were analyzed using the comparative CTmethod of relative quantification (Livak and Schmittgen, 2001) (Tables19 and 20).

TABLE 19 Relative serum F12 protein levels in mice followingadministration of canonical or UNA-containing RNAi trigger 1:1 with MLPdelivery polymer. Serum F12 levels were normalized to day 1 and salinecontrol. Treatment Day −1 Day 8 Saline 1.00 ± 0.00 1.00 ± 0.38 AD009001.00 ± 0.00 0.01 ± 0.00 AD01000 1.00 ± 0.00 0.01 ± 0.00 AD01001 1.00 ±0.00 0.01 ± 0.00 AD01003 1.00 ± 0.00 0.02 ± 0.01

TABLE 20 Liver mF12 mRNA levels in mice following administration ofcanonical or UNA-containing RNAi trigger 1:1 wt./wt. with MLP deliverypolymer. F12 mRNA level is expressed relative to mouse β-actin mRNAlevel. Relative Expression Treatment day 8 Low error High error Saline1.00 −0.09 +0.09 AD00900 0.05 −0.01 +0.01 AD01000 0.04 −0.00 +0.01AD01001 0.03 −0.00 +0.00 AD01003 0.05 −0.00 +0.00 AD01520 2 0.07 0.01

Example 9. Examination of Pharmacodynamic (PD) Effects of F12 Reductionafter Treatment with F12 RNAi Triggers—Carrageenan Induced Paw Edema(CPE) in Rats

To test that reducing F12 levels leads to effects on thekallikrein/kinin system, we tested the effects of pre-treatment with F12RNAi triggers on an inflammation model (CPE) in rats. Inflammationinduced by λ carrageenan is induced by multiple mediators includingbradykinin. Wild-type rats were given a single IV dose of either 8 mg/kgRNAi trigger (AD01520) with 8 mg/kg MLP delivery polymer, or saline.After 7 days, carrageenan was injected into the rear paws of saline orRNAi trigger-treated rats, and paw volume was measured over 6 hours.Change in paw volume over time is plotted in FIG. 9. The difference inpaw volume changes between saline and F12 RNAi trigger-treated groupsare statistically significant (p<0.0001), and are similar to those seenwith treatment of kallikrein-targeted antibody (Kenniston J A et al2014), indicating a reduction of signaling through the kallikrein/kininsystem.

Example 10. Examination of Pharmacodynamic (PD) Effects of F12 Reductionafter Treatment with F12 RNAi Triggers—Ferric Chloride Challenge

A clinically relevant indicator of physiologic response to F12 knockdownis the thromboembolism model induced by Ferric Chloride treatment.Cholesterol-conjugated canonical RNAi triggers were administered towild-type mice as described above 7 days prior to Ferric Chloride(FeCl3) Challenge. Prior to FeCl3 challenge, F12 levels were measured.Treatment with 4 mg/kg AD01520 and 4 mg/kg MLP delivery polymer resultedin >99% knockdown of mF12 protein in the serum. Thrombosis is induced byexposure of the carotid artery (CA) to ferric chloride and time toocclusion of blood flow is measured by flow probe for up to 30 minutes.All mice treated with F12 RNAi trigger with MLP delivery polymer did notocclude during the timeframe of the experiment (FIG. 10).

Example 11. Examination of Pharmacodynamic (PD) Effects of F12 Reductionafter Treatment with F12 RNAi Triggers—Bleeding Risk

A potential risk of some anticoagulant treatments is an increased riskof bleeding events. A Factor VII (F7)-targeted RNAi trigger was used asa positive bleeding control, as F7 is known as a key component of theextrinsic coagulation pathway.

Wild-type mice were given a single IV dose of 8 mg/kg AD01520 with 8mg/kg MLP delivery polymer, or 8 mg/kg F7 trigger with 8 mg/kg MLPdelivery polymer 7 days prior to challenge. Transverse cut of the tailvein was performed, and time to clotting monitored up to 15 minutes.There was no significant difference in bleeding times between saline andAD01520 treated mice (FIG. 11).

Example 12. Factor 12 (F12) Knockdown in Non-Human Primates FollowingF12 RNAi Trigger Molecule Delivery with MLP Delivery Polymer

MLP delivery polymer and RNAi trigger were made and combined in apharmaceutically acceptable buffer as described above. On day 1, twocynomolgus macaque (Macaca fascicularis) primates (both male, 5.0 kg and8.15 kg, respectively) were co-injected with 2 mg/kg RNAi trigger(AD01001) and 2 mg/kg MLP delivery polymer. For each injection, the RNAitrigger+MLP delivery polymer (2 mg/kg) was injected into the saphenousvein using a 22 to 25 gauge intravenous catheter. At the indicated timepoints (indicated in Tables 21-23), blood samples were drawn andanalyzed for F12 levels, coagulation parameters and toxicity markers.Blood was collected from the femoral vein and primates were fastedovernight before all blood collections. Blood tests for blood ureanitrogen (BUN), alanine transaminase (ALT), aspartate aminotransferase(AST), creatinine, and activated Partial thromboplastin time (aPTT) wereperformed on an automated chemistry analyzer. F12 protein levels inserum were monitored by assaying serum from the monkeys using an ELISAfor human F12 (Molecular Innovations) until F12 expression levelsreturned to baseline. For normalization, F12 levels for each animal at arespective time point was divided by the pre-treatment level ofexpression in that animal (in this case at day 1) to determine the ratioof expression “normalized to day 1”. Functional readout of F12 knockdowncan also be observed through elongation of the activated partialthromboplastin time (aPTT). No changes in Prothrombin time were observedwith treatment.

Significant knockdown of F12 was observed with an average maximumknockdown of 92.5% observed at day 15. An increase in aPTT was observedin both animals with maximal increases over pre-bleed values between50-56% at days 15 and 22, although aPTT did not exceed “normal” values.No dose-related toxicity was observed in treated animals.

TABLE 21 Serum F12 protein levels in cynomolgus macaque (Macacafascicularis) primates following administration of 2 mg/kg AD01001 with2 mg/kg MLP delivery polymer. mF12 levels were normalized to pre-dose.pre- Day animal dose 3 8 15 22 29 36 43 50 57 64 71 78 85 1 1.00 0.590.13 0.09 0.13 0.20 0.44 0.60 0.58 0.68 1.50 1.46 1.59 1.63 2 1.00 0.420.14 0.06 0.08 0.11 0.22 0.25 0.42 0.51 0.70 0.76 0.91 1.01

TABLE 22 Activated Partial Thromboplastin Time (sec) in cynomolgusmacaque (Macaca fascicularis) primates following administration of 2mg/kg AD01001 with 2 mg/kg MLP delivery polymer. Day animal pre-dose 3 815 22 29 36 43 50 57 1 32.2 35.4 44.9 48.6 47.5 39.9 42.9 34.3 38.3. 272 29.6 25.0 32.0 42.2 46.3 47.4 42.5 45.0 38.1 29.4

TABLE 23 Urea Nitrogen, Creatinine, Alanine transaminase, and Aspartateaminotransferase levels in cynomolgus macaque (Macaca fascicularis)primates following administration of 2 mg/kg AD01001 with 2 mg/kg MLPdelivery polymer. day animal pre-dose 3 8 15 22 29 36 43 50 57 BloodUrea Nitrogen (mg/dL) 1 13 13 12 13 14 13 13 14 14 14 2 18 17 15 17 1614 18 17 19 18 Creatinine (mg/dL) 1 0.76 0.69 0.76 0.79 0.78 0.77 0.770.75 0.69 0.78 2 1.03 1.05 0.04 0.99 0.98 1.00 1.08 1.02 1.03 1.01Alanine transaminase (U/L) 1 45 45 44 43 42 45 45 44 42 41 2 40 44 45 4138 47 54 50 49 52 Aspartate aminotransferase (U/L) 1 24 27 22 24 28 2421 31 27 22 2 25 23 23 22 30 22 21 21 24 22

Example 13. Factor 12 (F12) Knockdown in Non-Human Primates FollowingF12 RNAi Trigger Molecule Delivery

MLP delivery polymer and RNAi trigger were made and combined in apharmaceutically acceptable buffer as described above. On day 1, twocynomolgus macaque (Macaca fascicularis) primates were co-injected witheither 2 mg/kg AD01001 and 2 mg/kg MLP delivery polymer, or 2 mg/kgAD01520 and 2 mg/kg MLP delivery polymer as described above. Bloodsamples were drawn and analyzed for F12 levels, coagulation parametersand toxicity markers. Blood was collected from the femoral vein andprimates were fasted overnight before all blood collections. Blood testsfor blood urea nitrogen (BUN), alanine transaminase (ALT), aspartateaminotransferase (AST), creatinine, and activated Partial thromboplastintime (aPTT) were performed on an automated chemistry analyzer. F12protein levels in serum were monitored by assaying serum from themonkeys using an ELISA for human F12 (Molecular Innovations) until F12expression levels returned to baseline. For normalization, F12 levelsfor each animal at a respective time point was divided by thepre-treatment level of expression in that animal (in this case at day 1)to determine the ratio of expression “normalized to day 1”. Functionalreadout of F12 knockdown can also be observed through elongation of theactivated partial thromboplastin time (aPTT). No changes in prothrombintime (PT) were observed with treatment.

Significant knockdown of F12 was observed with an average maximumknockdown of 89% observed at day 15 (FIG. 5). An increase in aPTT wasobserved in both animals with maximal increases over pre-bleed values ofapproximately 70%-80% at days 15 and 22, although aPTT did not exceed“normal” values. No dose-related toxicity was observed in treatedanimals.

Example 14. Factor 12 (F12) Knockdown in Non-Human Primates FollowingF12 RNAi Trigger Molecule Delivery

MLP delivery polymer and RNAi trigger were made and combined in apharmaceutically acceptable buffer as described above. On days 1, 29,57, 85, two cynomolgus macaque (Macaca fascicularis) primates wereco-injected with either 2 mg/kg AD01001 and 2 mg/kg MLP deliverypolymer, or 2 mg/kg AD01520 and 2 mg/kg MLP delivery polymer asdescribed above. Blood samples were drawn and analyzed for F12 levels,coagulation parameters and toxicity markers. Blood was collected fromthe femoral vein and primates were fasted overnight before all bloodcollections. Blood tests for blood urea nitrogen (BUN), alaninetransaminase (ALT), aspartate aminotransferase (AST), creatinine, andboth prothrombin time (PT) and activated Partial thromboplastin time(aPTT) were performed on an automated chemistry analyzer. F12 proteinlevels in serum were monitored by assaying serum from the monkeys usingan ELISA for human F12 (Molecular Innovations) until F12 expressionlevels returned to baseline. For normalization, F12 levels for eachanimal at a respective time point was divided by the pre-treatment levelof expression in that animal (in this case at day 1) to determine theratio of expression “normalized to day 1”. Functional readout of F12knockdown can also be observed through elongation of the activatedpartial thromboplastin time (aPTT). No changes in Prothrombin time wereobserved with treatment.

Significant knockdown of F12 was observed with an average maximumknockdown between 85-93% observed at day 15, and between 95-98% onsubsequent doses (FIG. 6). An increase in aPTT was observed in bothanimals with maximal increases over pre-bleed values observed when F12levels are at nadir (FIG. 7). No dose-related toxicity nor increase inPT was observed in treated animals over the time of the experiment.

Example 15. Factor 12 (F12) Knockdown in Non-Human Primates FollowingF12 RNAi Trigger Molecule Delivery

RNAi trigger was made and combined in a pharmaceutically acceptablebuffer as described above for subcutaneous (SQ) injection. On day 1, twocynomolgus macaque (Macaca fascicularis) primates were injected witheither 3 mg/kg AD02562, or 10 mg/kg AD02562 subcutaneously. Bloodsamples were drawn and analyzed for F12 levels, coagulation parametersand toxicity markers as previously described.

Knockdown of F12 was observed with an average maximum knockdown of 60%for the 3 mg/kg dose and 84% for the 10 mg/kg dose, observed betweendays 22 and day 29 (FIG. 8). No dose-related toxicity nor increase in PTwas observed in treated animals over the duration of the experiment.

Example 16

Examples of F12 RNAi trigger duplexes.

TABLE 24 F12 RNAi triggers identified by Duplex ID No. withcorresponding sense and antisense strands. Antisense Sense StrandAntisense Sense Strand Duplex ID Strand ID ID Duplex ID Strand ID IDAD00638 AM01377-AS AM01307-SS AD00873 AM01556-AS AM01513-SS AD00639AM01378-AS AM01308-SS AD01227 AM02060-AS AM02061-SS AD00640 AM01379-ASAM01309-SS AD01228 AM02062-AS AM02063-SS AD00641 AM01380-AS AM01310-SSAD01269 AM02112-AS AM00923-SS AD00642 AM01381-AS AM01311-SS AD01270AM02113-AS AM00923-SS AD00643 AM01382-AS AM01312-SS AD01302 AM02164-ASAM02168-SS AD00644 AM01383-AS AM01313-SS AD01304 AM02166-AS AM02168-SSAD00645 AM01384-AS AM01314-SS AD01305 AM02167-AS AM02168-SS AD00646AM01385-AS AM01315-SS AD01306 AM02164-AS AM02169-SS AD00647 AM01386-ASAM01316-SS AD01308 AM02166-AS AM02169-SS AD00648 AM01387-AS AM01317-SSAD01309 AM02167-AS AM02169-SS AD00649 AM01388-AS AM01318-SS AD01480AM02165-AS AM02459-SS AD00650 AM01389-AS AM01319-SS AD01481 AM02460-ASAM02459-SS AD00651 AM01390-AS AM01320-SS AD01482 AM02461-AS AM02459-SSAD00652 AM01391-AS AM01321-SS AD01483 AM02462-AS AM02459-SS AD00653AM01392-AS AM01322-SS AD01551 AM02579-AS AM02581-SS AD00654 AM01393-ASAM01323-SS AD01552 AM02582-AS AM02584-SS AD00655 AM01394-AS AM01324-SSAD01553 AM02585-AS AM02274-SS AD00656 AM01395-AS AM01325-SS AD01584AM02641-AS AM01617-SS AD00657 AM01396-AS AM01326-SS AD01585 AM02642-ASAM01617-SS AD00658 AM01397-AS AM01327-SS AD01586 AM02643-AS AM01617-SSAD00659 AM01399-AS AM01328-SS AD01587 AM02644-AS AM01617-SS AD00660AM01400-AS AM01329-SS AD01588 AM02645-AS AM01617-SS AD00661 AM01401-ASAM01330-SS AD01589 AM02646-AS AM01617-SS AD00662 AM01402-AS AM01331-SSAD01590 AM02647-AS AM01617-SS AD00663 AM01403-AS AM01332-SS AD01591AM02648-AS AM01617-SS AD00664 AM01404-AS AM01333-SS AD01592 AM02645-ASAM02649-SS AD00665 AM01405-AS AM01334-SS AD01593 AM02646-AS AM02649-SSAD00666 AM01406-AS AM01335-SS AD01594 AM02647-AS AM02649-SS AD00667AM01407-AS AM01336-SS AD01595 AM02648-AS AM02649-SS AD00668 AM01408-ASAM01337-SS AD01596 AM00988-AS AM02649-SS AD00669 AM01409-AS AM01338-SSAD01597 AM01629-AS AM02649-SS AD00670 AM01410-AS AM01339-SS AD01606AM02208-AS AM02654-SS AD00671 AM01411-AS AM01340-SS AD01609 AM02656-ASAM02654-SS AD00672 AM01412-AS AM01341-SS AD01625 AM02660-AS AM02664-SSAD00673 AM01413-AS AM01342-SS AD01626 AM02661-AS AM02664-SS AD00674AM01414-AS AM01343-SS AD01631 AM02660-AS AM02665-SS AD00675 AM01415-ASAM01344-SS AD01632 AM02661-AS AM02665-SS AD00676 AM01416-AS AM01345-SSAD01634 AM02657-AS AM02666-SS AD00677 AM01417-AS AM01346-SS AD01660AM02691-AS AM02723-SS AD00678 AM01418-AS AM01347-SS AD01661 AM02692-ASAM02724-SS AD00679 AM01419-AS AM01348-SS AD01662 AM02693-AS AM02725-SSAD00680 AM01420-AS AM01349-SS AD01663 AM02694-AS AM02726-SS AD00681AM01421-AS AM01350-SS AD01664 AM02695-AS AM02727-SS AD00682 AM01422-ASAM01351-SS AD01665 AM02696-AS AM02728-SS AD00683 AM01423-AS AM01352-SSAD01666 AM02697-AS AM02729-SS AD00684 AM01424-AS AM01353-SS AD01667AM02698-AS AM02730-SS AD00685 AM01425-AS AM01354-SS AD01668 AM02699-ASAM02731-SS AD00686 AM01426-AS AM01355-SS AD01669 AM02700-AS AM02732-SSAD00687 AM01427-AS AM01356-SS AD01670 AM02701-AS AM02733-SS AD00688AM01428-AS AM01357-SS AD01671 AM02702-AS AM02734-SS AD00689 AM01429-ASAM01358-SS AD01672 AM02703-AS AM02735-SS AD00690 AM01430-AS AM01359-SSAD01673 AM02704-AS AM02736-SS AD00691 AM01431-AS AM01360-SS AD01674AM02705-AS AM02737-SS AD00692 AM01432-AS AM01361-SS AD01675 AM02706-ASAM02738-SS AD00693 AM01433-AS AM01362-SS AD01676 AM02707-AS AM02723-SSAD00694 AM01434-AS AM01363-SS AD01677 AM02708-AS AM02724-SS AD00695AM01435-AS AM01364-SS AD01678 AM02709-AS AM02725-SS AD00696 AM01436-ASAM01365-SS AD01679 AM02710-AS AM02726-SS AD00697 AM01437-AS AM01366-SSAD01680 AM02711-AS AM02727-SS AD00698 AM01438-AS AM01367-SS AD01681AM02712-AS AM02728-SS AD00699 AM01439-AS AM01368-SS AD01682 AM02713-ASAM02729-SS AD00700 AM01440-AS AM01369-SS AD01683 AM02714-AS AM02730-SSAD00701 AM01441-AS AM01370-SS AD01684 AM02715-AS AM02731-SS AD00702AM01442-AS AM01371-SS AD01685 AM02716-AS AM02732-SS AD00703 AM01443-ASAM01372-SS AD01686 AM02717-AS AM02733-SS AD00704 AM01444-AS AM01373-SSAD01687 AM02718-AS AM02734-SS AD00705 AM01445-AS AM01374-SS AD01688AM02719-AS AM02735-SS AD00706 AM01446-AS AM01375-SS AD01689 AM02720-ASAM02736-SS AD00707 AM01447-AS AM01376-SS AD01690 AM02721-AS AM02737-SSAD00831 AM01514-AS AM01471-SS AD01691 AM02722-AS AM02738-SS AD00832AM01515-AS AM01472-SS AD01692 AM02707-AS AM02739-SS AD00833 AM01516-ASAM01473-SS AD01693 AM02708-AS AM02740-SS AD00834 AM01517-AS AM01474-SSAD01694 AM02709-AS AM02741-SS AD00835 AM01518-AS AM01475-SS AD01695AM02710-AS AM02742-SS AD00836 AM01519-AS AM01476-SS AD01696 AM02711-ASAM02743-SS AD00837 AM01520-AS AM01477-SS AD01697 AM02712-AS AM02744-SSAD00838 AM01521-AS AM01478-SS AD01698 AM02713-AS AM02745-SS AD00839AM01522-AS AM01479-SS AD01699 AM02714-AS AM02746-SS AD00840 AM01523-ASAM01480-SS AD01700 AM02715-AS AM02747-SS AD00841 AM01524-AS AM01481-SSAD01701 AM02716-AS AM02748-SS AD00842 AM01525-AS AM01482-SS AD01702AM02717-AS AM02749-SS AD00843 AM01526-AS AM01483-SS AD01703 AM02718-ASAM02750-SS AD00844 AM01527-AS AM01484-SS AD01704 AM02719-AS AM02751-SSAD00845 AM01528-AS AM01485-SS AD01705 AM02720-AS AM02752-SS AD00846AM01529-AS AM01486-SS AD01706 AM02721-AS AM02753-SS AD00847 AM01530-ASAM01487-SS AD01707 AM02722-AS AM02754-SS AD00848 AM01531-AS AM01488-SSAD01781 AM02871-AS AM02500-SS AD00849 AM01532-AS AM01489-SS AD01782AM02871-AS AM02872-SS AD00850 AM01533-AS AM01490-SS AD01783 AM02507-ASAM02872-SS AD00851 AM01534-AS AM01491-SS AD01833 AM02953-AS AM02955-SSAD00852 AM01535-AS AM01492-SS AD01906 AM02656-AS AM03054-SS AD00853AM01536-AS AM01493-SS AD01907 AM02656-AS AM03055-SS AD00854 AM01537-ASAM01494-SS AD01908 AM02656-AS AM03057-SS AD00855 AM01538-AS AM01495-SSAD01909 AM02847-AS AM02872-SS AD00856 AM01539-AS AM01496-SS AD01950AM02656-AS AM03044-SS AD00857 AM01540-AS AM01497-SS AD01951 AM02656-ASAM03032-SS AD00858 AM01541-AS AM01498-SS AD01952 AM02656-AS AM03033-SSAD00859 AM01542-AS AM01499-SS AD01995 AM02656-AS AM03138-SS AD00860AM01543-AS AM01500-SS AD01996 AM02656-AS AM03139-SS AD00861 AM01544-ASAM01501-SS AD01997 AM02656-AS AM03140-SS AD00862 AM01545-AS AM01502-SSAD01998 AM02656-AS AM03141-SS AD00863 AM01546-AS AM01503-SS AD02048AM02656-AS AM03180-SS AD00864 AM01547-AS AM01504-SS AD02631 AM03157-ASAM03372-SS AD00865 AM01548-AS AM01505-SS AD02632 AM03157-AS AM03373-SSAD00866 AM01549-AS AM01506-SS AD02633 AM03157-AS AM03374-SS AD00867AM01550-AS AM01507-SS AD02641 AM03157-AS AM03401-SS AD00868 AM01551-ASAM01508-SS AD02660 AM03410-AS AM03421-SS AD00869 AM01552-AS AM01509-SSAD02742 AM03157-AS AM03540-SS AD00870 AM01553-AS AM01510-SS AD02743AM03157-AS AM03541-SS AD00871 AM01554-AS AM01511-SS AD02818 AM03644-ASAM03436-SS AD00872 AM01555-AS AM01512-SS AD02980 AM03803-AS AM03653-SSAD02833 AM03662-AS AM03402-SS AD02981 AM03804-AS AM03653-SS AD02834AM03663-AS AM03402-SS AD02982 AM03805-AS AM03653-SS AD02835 AM03664-ASAM03402-SS AD02983 AM03581-AS AM03778-SS AD02836 AM03665-AS AM03402-SSAD02984 AM03787-AS AM03806-SS AD02837 AM03666-AS AM03402-SS AD02985AM03581-AS AM03807-SS AD02838 AM03667-AS AM03402-SS AD02986 AM03808-ASAM03653-SS AD02839 AM03157-AS AM03669-SS AD02987 AM03808-AS AM03807-SSAD02840 AM03668-AS AM03402-SS AD02988 AM03809-AS AM03726-SS AD02856AM03157-AS AM03684-SS AD02989 AM03810-AS AM03726-SS AD02867 AM03157-ASAM03703-SS AD02990 AM03811-AS AM03726-SS AD02868 AM03157-AS AM03704-SSAD02992 AM02711-AS AM03813-SS AD02869 AM03589-AS AM03705-SS AD02993AM02711-AS AM03814-SS AD02870 AM03590-AS AM03705-SS AD02994 AM02711-ASAM03815-SS AD02871 AM03590-AS AM03706-SS AD02995 AM02711-AS AM03816-SSAD02885 AM02711-AS AM03729-SS AD02996 AM02711-AS AM03817-SS AD02886AM03359-AS AM03729-SS AD02997 AM02711-AS AM03818-SS AD02887 AM02711-ASAM03730-SS AD02998 AM03809-AS AM03812-SS AD02888 AM03359-AS AM03730-SSAD02999 AM03810-AS AM03812-SS AD02889 AM03732-AS AM03726-SS AD03000AM03811-AS AM03812-SS AD02890 AM03736-AS AM03726-SS AD03001 AM03809-ASAM03815-SS AD02891 AM03732-AS AM03729-SS AD03002 AM03810-AS AM03815-SSAD02892 AM03736-AS AM03729-SS AD03003 AM03811-AS AM03815-SS AD02893AM03349-AS AM03726-SS AD03004 AM03809-AS AM03818-SS AD02894 AM03350-ASAM03726-SS AD03005 AM03810-AS AM03818-SS AD02895 AM03351-AS AM03726-SSAD03006 AM03811-AS AM03818-SS AD02896 AM03733-AS AM03726-SS AD03007AM03819-AS AM03653-SS AD02897 AM03353-AS AM03726-SS AD03008 AM03820-ASAM03653-SS AD02898 AM03734-AS AM03726-SS AD03009 AM03821-AS AM03653-SSAD02899 AM03359-AS AM03727-SS AD03010 AM03822-AS AM03653-SS AD02900AM03359-AS AM03728-SS AD03014 AM03832-AS AM03726-SS AD02901 AM03735-ASAM03731-SS AD03015 AM03833-AS AM03726-SS AD02902 AM03737-AS AM03731-SSAD03016 AM03832-AS AM03834-SS AD02903 AM03157-AS AM03738-SS AD03017AM03833-AS AM03834-SS AD02904 AM03157-AS AM03739-SS AD03018 AM02711-ASAM03834-SS AD02905 AM03732-AS AM03730-SS AD03019 AM03581-AS AM03632-SSAD02906 AM03736-AS AM03730-SS AD03020 AM03581-AS AM03836-SS AD02950AM03581-AS AM03654-SS AD03021 AM03787-AS AM03836-SS AD02951 AM03581-ASAM03775-SS AD03022 AM03581-AS AM03838-SS AD02952 AM03785-AS AM03653-SSAD03023 AM03581-AS AM03840-SS AD02953 AM03786-AS AM03775-SS AD03024AM03581-AS AM03842-SS AD02954 AM03581-AS AM03776-SS AD03025 AM03581-ASAM03844-SS AD02955 AM03581-As AM03777-SS AD03026 AM03803-AS AM03632-SSAD02956 AM03787-AS AM03776-SS AD03027 AM03804-AS AM03632-SS AD02957AM03785-AS AM03778-SS AD03028 AM03805-AS AM03632-SS AD02958 AM03581-ASAM03779-SS AD03029 AM03581-AS AM03846-SS AD02959 AM03788-AS AM03653-SSAD03030 AM03581-AS AM03848-SS AD02960 AM03581-AS AM03780-SS AD03031AM03581-AS AM03850-SS AD02961 AM03789-AS AM03775-SS AD03032 AM03851-ASAM03632-SS AD02962 AM03789-AS AM03781-SS AD03033 AM03852-AS AM03632-SSAD02963 AM03581-AS AM03781-SS AD03034 AM03853-AS AM03632-SS AD02964AM03790-AS AM03781-SS AD03035 AM03854-AS AM03632-SS AD02965 AM03791-ASAM03775-SS AD03036 AM03851-AS AM03846-SS AD02966 AM03792-AS AM03775-SSAD03037 AM03852-AS AM03846-SS AD02967 AM03793-AS AM03775-SS AD03038AM03853-AS AM03846-SS AD02968 AM03794-AS AM03775-SS AD03039 AM03854-ASAM03846-SS AD02969 AM03581-AS AM03782-SS AD03040 AM03851-AS AM03848-SSAD02970 AM03581-AS AM03783-SS AD03041 AM03852-AS AM03848-SS AD02971AM03581-AS AM03784-SS AD03042 AM03853-AS AM03848-SS AD02972 AM03795-ASAM03775-SS AD03043 AM03854-AS AM03848-SS AD02973 AM03796-AS AM03775-SSAD03044 AM03851-AS AM03850-SS AD02974 AM03797-AS AM03775-SS AD03045AM03852-AS AM03850-SS AD02975 AM03798-AS AM03775-SS AD03046 AM03853-ASAM03850-SS AD02976 AM03799-AS AM03402-SS AD03047 AM03854-AS AM03850-SSAD02977 AM03581-AS AM03800-SS AD03048 AM03855-AS AM03402-SS AD02978AM03581-AS AM03801-SS AD03076 AM03851-AS AM03886-SS AD02979 AM03581-ASAM03802-SS

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. An RNA interference (RNAi) trigger capable of inhibiting theexpression of an Factor XII (F12) gene wherein said RNAi triggercomprises a sense strand and an antisense strand, and wherein saidantisense strand comprises any of the antisense sequences in Table 1 andTable
 2. 2. The RNAi trigger of claim 1, wherein the RNAi triggercomprises at least one modified nucleotide.
 3. The RNAi trigger of claim2, wherein the at least one modified nucleotide is selected from thegroup consisting of: 2′-O-methyl nucleotide, 2′-Fluoro nucleotide,2′-deoxy nucleotide, 2′,3′-seco nucleotide mimic, locked nucleotide,2′-F-Arabino nucleotide, 2′-methoxyethyl nucleotide, abasic ribose,ribitol, inverted nucleotide, inverted abasic nucleotide, inverted2′-OMe nucleotide, inverted 2′-deoxy nucleotide, 2′-amino-modifiednucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, vinylphosphonate deoxyribonucleotide, and 3′-OMe nucleotide.
 4. The RNAitrigger of claim 1, wherein the sense strand contains one, two, or three2′-F nucleotides at positions 11, 12, and/or 13 from the 3′ end.
 5. TheRNAi trigger of claim 1, wherein the antisense strand contains a 2′-Fnucleotide at position 2 from the 5′ end.
 6. The RNAi trigger of claim1, wherein the antisense strand contains a 2′-F nucleotide at position14 from the 5′ end.
 7. The RNAi trigger of claim 1, wherein theantisense strand contains one, two, three, or four 2′-F nucleotides atpositions 4, 6, 8, 10, and 12 from the 5′ end.
 8. The RNAi trigger ofclaim 1, wherein the RNAi trigger comprises one or more phosphorothioateintemucleotide linkages.
 9. The RNAi trigger of claim 1, wherein thesense strand comprises one or two phosphorothioate intemucleotidelinkages.
 10. The RNAi trigger of claim 1, wherein the antisense strandcontains one, two, three, or four phosphorothioate intemucleotidelinkages.
 11. The RNAi trigger of claim 1, further comprising atargeting group conjugated to the sense strand.
 12. The RNAi triggermolecule of claim 11, wherein the targeting group comprises acholesterol or cholesteryl derivative.
 13. The RNAi trigger of claim 11,wherein a targeting group comprises an asialoglycoprotein receptorligand.
 14. The RNAi trigger of claim 13, wherein the asialoglycoproteinreceptor ligand comprises a galactose cluster.
 15. The RNAi trigger ofclaim 14, wherein the galactose cluster comprises anN-acetyl-galactosamine trimer.
 16. The RNAi trigger of claim 15, whereinthe N-acetyl-galactosamine trimer has a structure selected from thegroup consisting of: NAG3, NAG13, NAG14, NAG15, NAG16, NAG17, NAG18,NAG19, NAG20, NAG21, NAG23, and NAG4.
 17. The RNAi trigger of claim 1,wherein the RNAi trigger comprises AD01520, AD02023, AD00900, AD01001,AD02639, AD02640, AD02642, AD02708, AD02807, AD02822, AD02867, orAD02868.
 18. The RNAi trigger of claim 1, wherein antisense strandcomprises the nucleotide sequence of SEQ ID No. 177, SEQ ID No. 150, orSEQ ID No.
 11. 19. The RNAi trigger of claim 1, wherein sense strandcomprises the nucleotide sequence of SEQ ID No. 374 or SEQ ID No. 379.20. A composition comprising: RNA interference (RNAi) trigger moleculecapable of inhibiting the expression of an Factor XII gene, wherein saidRNAi trigger molecule comprises a sense strand and an antisense strand,wherein said antisense strand comprises any of the antisense sequencesin Table 1 and Table 2, and at least one pharmaceutically acceptableexcipient.
 21. The composition of claim 20, wherein the at least onepharmaceutically acceptable excipient includes a delivery polymer. 22.The composition of claim 21, wherein the delivery polymer comprises amelittin-like peptide.
 23. The composition of claim 20, furthercomprising a second therapeutic or treatment.
 24. The composition ofclaim 20, wherein said composition is packaged in a kit, container,pack, dispenser, pre-filled syringes, or vials.
 25. The composition ofclaim 20, wherein said composition is administered parenterally.
 26. Amethod for inhibiting Factor XII expression in a subject comprising:administering to said subject a therapeutically effective amount of anRNA interference (RNAi) trigger capable of inhibiting the expression ofan F12 gene wherein said RNAi trigger comprises a sense strand and anantisense strand, wherein said antisense strand comprises any of theantisense sequences in Table 1 and Table
 2. 27. A method for thetreatment of angioedema, including hereditary angioedema and venousthromboembolism, comprising administering to a patient in need of suchtreatment the composition of claim
 1. 28. A method for the treatment ofangioedema, including hereditary angioedema and venous thromboembolism,comprising administering to a patient in need of such treatment thecomposition of claim 17.